Colchinol derivatives as vascular damaging agents

ABSTRACT

The invention relates to the use of compounds of formula (I): wherein X is —C(O)—, —C(S)—, —C═NOH, or —CH(R 7 )— wherein R 7  is hydrogen, hydroxy, C 1-7 alkoxy, —OR 8  or —NR 8 R 9  (wherein R 8  is a group —Y 1 R 10  (wherein Y 1  is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O, —C(O)NR 11 —, —SO 2 — or —SO 2 NR 12 — (wherein R 11  and R 12 , which may be the same or different, each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 10  is as defined herein, and R 9  includes hydrogen; R 1 , R 2  and R 3  are as defined herein and are preferably methyl; R 4 , R 5  and R 6  are as defined herein with the proviso that R 5  is not hydroxy, alkoxy, substituted alkoxy, —OPO 3 H 2 , —O—C 1-7 alkanoyl or benzyloxy; and salts thereof in the manufacture of a medicament for use in the production of a vascular damaging effect in warm-blooded animals such as humans. The present invention further relates to compounds of the formula (I), pharmaceutical compositions containing them, processes for their preparation and to a method of treatment using the compounds to produce a vascular damaging effect in a warm-blooded animal such as a human. The compounds of formula (I) and the pharmaceutically acceptable salts thereof may be useful in the treatment of a number of disease states including cancer and rheumatoid arthritis.

This application is a 371 of PCT/GB99/04436, filed Dec. 24, 1999, whichclaims priority to UK application 9900334.5, filed Jan. 7, 1999.

The present invention relates to vascular damaging agents, in particularto the use of compounds of the invention in the manufacture ofmedicaments for use in the production of antiangiogenic effects inwarm-blooded animals such as humans, to processes for the preparation ofsuch compounds, to pharmaceutical compositions containing such compoundsas active ingredient, to methods for the treatment of disease statesassociated with angiogenesis and to the use of such compounds asmedicaments.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 26: 57–66; Folkman,1995, Nature Medicine 1: 27–31). Formation of new vasculature byangiogenesis is a key pathological feature of several diseases (J.Folkman, New England Journal of Medicine 333, 1757–1763 (1995)). Forexample, for a solid tumour to grow it must develop its own blood supplyupon which it depends critically for the provision of oxygen andnutrients; if this blood supply is mechanically shut off the tumourundergoes necrotic death. Neovascularisation is also a clinical featureof skin lesions in psoriasis, of the invasive pannus in the joints ofrheumatoid arthritis patients and of atherosclerotic plaques. Retinalneovascularisation is pathological in macular degeneration and indiabetic retinopathy.

Reversal of neovascularisation by damaging the newly-formed vascularendothelium is expected to have a beneficial therapeutic effect. Thepresent invention is based on the discovery of tricyclic compounds thatsurprisingly specifically damage newly formed vasculature withoutaffecting the normal, established vascular endothelium of the hostspecies, a property of value in the treatment of disease statesassociated with angiogenesis such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation, endometriosis, dysfunctional uterine bleeding and oculardiseases with retinal vessel proliferation.

Compounds of the present invention are colchinol derivatives. Colchinolderivatives for example N-acetyl-colchinol are known. Anti-tumoureffects have been noted on animal models (see for example—Jnl. Natl.Cancer Inst. 1952, 13, 379–392). However, the effect studied was that ofgross damage (haemorrhage, softening and necrosis) and there is nosuggestion of treatment of inappropriate angiogenesis by destruction ofneovasculature.

A search of Chemical Abstracts (post 1955) based on the substructure:

revealed a number of colchinol related structures. To the extent thatany of these compounds have been studied for anti-cancer activity it isbecause tubulin-binding agents like colchinol might be expected to beanti-mitotic and therefore to have a direct effect on tumour cells. Somecompounds which bind tubulin have been shown to have anti-vasculareffects when given at their maximum tolerated dose (MTD) (S. A. Hill etal. Eur. J Cancer, 29A, 1320–1324 (1993)) but other tubulin-bindingagents have no vascular-damaging activity even when administered at theMTD, for example docetaxel (Lancet, 1994, 344, 1267–1271). Based on thisinformation and in the course of the work in the present invention, theissue of the relevance of tubulin-binding properties to possibleeffectiveness as anti-vascular agent was studied but no predictabilitywas found. No correlation between the potency of tubulin interaction andeffectiveness as an anti-vascular agent is apparent. Certain compoundsstructurally related to those of the present invention but not of thepresent invention, have been found to have a therapeutic window (ratioof MTD to minimum effective dose (MED)) too small for potential clinicaleffectiveness.

The presence of tubulin-binding properties is then not predictive forantivascular activity. Compounds which have strong tubulin-bindingactivity give rise to antimitotic effects in vivo. The effects of thisare most noticeable on proliferating tissue and give rise to undesirableeffects, for example on the proliferative tissue of the gut and bonemarrow. Compounds which have vascular damaging activity but weaktubulin-binding activity would therefore be useful in the treatment ofdiseases involving angiogenesis.

It is believed, though this is not limiting on the invention, that theuse of compounds of the invention damages newly-formed vasculature, forexample the vasculature of tumours, thus effectively reversing theprocess of angiogenesis as compared to known anti-angiogenic agentswhich tend to be less effective once the vasculature has formed.

According to one aspect of the present invention there is provided theuse of a compound of formula I:

wherein

-   X is —C(O)—, —C(S)—, —C═NOH, or —CH(R⁷)— wherein R⁷ is hydrogen,    hydroxy, C₁₋₇alkoxy, —OR⁸ or —NR⁸R⁹ (wherein R⁸ is a group —Y¹R¹⁰    (wherein Y¹ is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O—,    —C(O)NR¹¹—, —SO₂— or —SO₂NR¹²— (wherein R¹¹ and R¹², which may be    the same or different, each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ is selected from one of    the following nine groups:-   1) hydrogen, C₁₋₇alkyl, C₃₋₇cycloalkyl, C₁₋₄alkylY⁸C₁₋₄alkyl wherein    Y⁸ is as defined hereinafter, or phenyl,    -   (which alkyl, cycloalkyl, alkylY⁸alkyl or phenyl group may bear        one or more substituents selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, carboxy, carbamoyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            phenyl, nitro, sulphate, phosphate,        -   Z¹ (wherein Z¹ represents a 5–6 membered saturated            heterocyclic group (linked via carbon or nitrogen) with 1–2            heteroatoms, selected independently from O, S and N, which            heterocyclic group may bear 1 or 2 substituents selected            from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,                C₁₋₄alkylsulphonylC₁₋₄alkyl and Z² (wherein Z² is a                5–6-membered saturated heterocyclic group (linked via                carbon or nitrogen) with 1–2 heteroatoms, selected                independently from O, S and N, which heterocyclic group                may bear 1 or 2 substituents selected from                -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                    C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                    cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl and                    C₁₋₄alkylsulphonylC₁₋₄alkyl)),        -   C₁₋₄alkylZ¹ (wherein Z¹ is as defined hereinbefore), and        -   a group —Y²R¹³ (wherein Y² is —NR¹⁴C(O)— or —O—C(O)—            (wherein R¹⁴ represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is C₁₋₇alkyl, C₃₋₇cycloalkyl or            a group R¹⁵ wherein R¹⁵ is a phenyl group or a 5–10-membered            aromatic heterocyclic group (linked via carbon or nitrogen)            with 1–4 heteroatoms selected independently from O, N and S,            which phenyl or aromatic heterocyclic group may bear one or            more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR¹⁶R¹⁷ and —NR¹⁸COR¹⁹            (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl)));-   2) R¹⁵ wherein R¹⁵ is as defined hereinbefore;-   3) C₂₋₇alkenylR¹⁵ (wherein R¹⁵ is as defined hereinbefore);-   4) C₃₋₇alkynylR¹⁵ (wherein R¹⁵ is as defined hereinbefore));-   5) Z¹ (wherein Z¹ is as defined hereinbefore);-   6) C₁₋₇alkylZ¹ (wherein Z¹ is as defined hereinbefore);-   7) C₁₋₇alkylY⁸Z¹ (wherein Z¹ is as defined hereinbefore and Y⁸ is    —C(O)—, —NR⁵⁹C(O)—, —NR⁵⁹C(O)C₁₋₄alkyl-, —C(O)NR⁶⁰— or    —C(O)NR⁶⁰C₁₋₄alkyl-, (wherein R⁵⁹ and R⁶⁰, which may be the same or    different, each represents hydrogen, C₁₋₃alkyl, C₁₋₃hydroxyalkyl or    C₁₋₃alkoxyC₂₋₃alkyl));-   8) (C₁₋₇alkyl)_(c)Y⁹Z³ (wherein c is 0 or 1, Z³ is an amino acid    group and Y⁹ is a direct bond, —C(O)— or —NR⁶¹— (wherein R⁶¹ is    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and-   9) C₁₋₇alkylR¹⁵ (wherein R¹⁵ is as defined hereinbefore);-   and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl or    cycloalkyl group may bear one or more substituents selected from    C₁₋₄alkoxy and phenyl);-   R¹, R² and R³ are each independently-   hydrogen, PO₃H₂, sulphate, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,    C₁₋₇alkanoyl, a group R²⁰C₁₋₇alkyl (wherein R²⁰ is phenyl which may    bear one or more substituents selected from C₁₋₄alkyl, C₁₋₄alkoxy,    C₁₋₄aminoalkyl and C₁₋₄hydroxyalkoxy), C₁₋₇alkyl or    C₁₋₇alkylsulphonyl    -   (which alkyl or alkylsulphonyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        carboxy, phenyl, nitro, sulphate, phosphate and a group —Y²R²¹        (wherein Y² is —NR²²C(O)— or —O—C(O)— (wherein R²² represents        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is        C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R²³ wherein R²³ is a phenyl        group or a 5–10-membered aromatic heterocyclic group (linked via        carbon or nitrogen) with 1–4 heteroatoms selected independently        from O, N and S, which phenyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR²⁴R²⁵ and —NR²⁶COR²⁷        (wherein R²⁴, R²⁵, R²⁶ and R²⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)));-   with the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl;-   R⁴, R⁵ and R⁶ are each independently selected from:-   hydrogen, —OPO₃H₂, phosphonate, cyano, halogeno, nitro, amino,    carboxy, carbamoyl, hydroxy, C₁₋₇alkoxy, C₁₋₇alkanoyl,    C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))), and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —C₁₋₄alkylNR³⁶—, —C₁₋₄alkylC(O)—, —NR³⁷C(O)—, —OC(O)O—,        —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein R³⁶, R³⁷, R³⁸ and R³⁹, which        may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    -   R³⁵ is a sugar moiety, a mono-peptide, a di-peptide, a        tri-peptide, a tetra-peptide, sulphate, hydroxy, amino,        C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇alkylamino,        di(C₁₋₇alkyl)amino, aminoC₁₋₇alkylamino,        C₁₋₇alkylaminoC₁₋₇alkylamino, C₁₋₇alkanoylaminoC₁₋₇alkyl,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate,        C₁₋₇alkylphosphonate, C₁₋₇alkylcarbamoylC₁₋₇alkyl,        -   (which alkyl, alkoxy, alkanoyl, alkylamino, dialkylamino,            aminoalkylamino, alkylaminoalkylamino, alkanoylaminoalkyl,            dialkylaminoalkylamino, alkylphosphate, alkylphosphonate or            alkylcarbamoylalkyl, may bear one or more substituents            selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            carboxy, phenyl, nitro, sulphate, phosphate and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or            —O—C(O)— (wherein R⁴¹ and R⁴² which may be the same or            different each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is C₁₋₇alkyl, C₃₋₇cycloalkyl,            carboxyC₁₋₇alkyl or a group R⁴³ wherein R⁴³ is a phenyl            group, a benzyl group or a 5–10-membered aromatic            heterocyclic group (linked via carbon or nitrogen) with 1–4            heteroatoms selected independently from O, N and S, which            phenyl, benzyl or aromatic heterocyclic group may bear one            or more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷            (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from        -   hydroxy, nitro, halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl,            di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,            di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy,            carboxy, C₁₋₄carboxyalkyl, phenyl, cyano, —CONR⁴⁹R⁵⁰,            —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the            same or different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (wherein R⁵³ is as            defined hereinafter),    -   C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as defined hereinbefore),    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from        -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,            C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴ (wherein R⁵⁴ is a            5–6-membered saturated heterocyclic group (linked via carbon            or nitrogen) with 1–2 heteroatoms, selected independently            from O, S and N, which heterocyclic group may bear 1 or 2            substituents selected from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and                C₁₋₄alkylsulphonylC₁₋₄alkyl)), or    -   (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³ (wherein R⁵³ is as defined hereinbefore,        a is 0, or an integer 1–4, b is 0 or an integer 1–4 and Y⁶        represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or        —C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl), and wherein one or more of the (CH₂)_(a)        or (CH₂)_(b) groups may bear one or more substituents selected        from hydroxy, amino and halogeno));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy    (wherein R⁵ is Y⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one    or more substituents selected from the list given hereinbefore),    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy;    and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof in the    manufacture of a medicament for use in the production of a vascular    damaging effect in warm-blooded animals such as humans.

According to a further aspect of the present invention there is providedthe use of a compound of the formula I as defined hereinbefore and saltsthereof, pharmaceutically acceptable salts thereof, solvates andhydrates thereof, and prodrugs thereof in the manufacture of amedicament for use in the production of a vascular damaging effect atless than the maximum tolerated dose in warm-blooded animals such ashumans. Conveniently X is —C(O)—, —C(S)— or —CH(R⁷)— wherein R⁷ ishydrogen, hydroxy, —OR⁸ or —NR⁸R⁹ (wherein R⁸ is a group —Y¹R¹⁰ (whereinY¹ is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O—, —C(O)NR¹¹—, —SO₂— or—SO₂NR¹²— (wherein R¹¹ and R¹², which may be the same or different, eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹⁰ is selected from one of the following seven groups:

-   1) hydrogen, C₁₋₇alkyl, C₃₋₇cycloalkyl, C₁₋₄alkylY⁸C₁₋₄alkyl wherein    Y⁸ is as defined hereinafter, or phenyl,    -   (which alkyl, cycloalkyl, alkylY⁸alkyl or phenyl group may bear        one or more substituents selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, carboxy, carbamoyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            phenyl, nitro, sulphate, phosphate,        -   Z¹ (wherein Z¹ represents a 5–6 membered saturated            heterocyclic group (linked via carbon or nitrogen) with 1–2            heteroatoms, selected independently from O, S and N, which            heterocyclic group may bear 1 or 2 substituents selected            from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,                C₁₋₄alkylsulphonylC₁₋₄alkyl and Z² (wherein Z² is a                5–6-membered saturated heterocyclic group (linked via                carbon or nitrogen) with 1–2 heteroatoms, selected                independently from O, S and N, which heterocyclic group                may bear 1 or 2 substituents selected from                -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                    C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                    cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl and                    C₁₋₄alkylsulphonylC₁₋₄alkyl)),        -   C₁₋₄alkylZ¹ (wherein Z¹ is as defined hereinbefore), and        -   a group —Y²R¹³ (wherein Y² is —NR¹⁴C(O)— or —O—C(O)—            (wherein R¹⁴ represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is C₁₋₇alkyl, C₃₋₇cycloalkyl or            a group R¹⁵ wherein R¹⁵ is a 5–10-membered aromatic            heterocyclic group (linked via carbon or nitrogen) with 1–4            heteroatoms selected independently from O, N and S, aromatic            heterocyclic group may bear one or more substituents            selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,            C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano,            —CONR¹⁶R¹⁷ and —NR¹⁸COR¹⁹ (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹,            which may be the same or different, each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)));-   2) R¹⁵ wherein R¹⁵ is as defined hereinbefore;-   3) Z¹ (wherein Z¹ is as defined hereinbefore);-   4) C₁₋₇alkylZ¹ (wherein Z¹ is as defined hereinbefore);-   5) C₁₋₇alkylY⁸Z¹ (wherein Z¹ is as defined hereinbefore and Y⁸ is    —C(O)—, —NR⁵⁹C(O)—, —NR⁵⁹C(O)C₁₋₄alkyl-, —C(O)NR⁶⁰— or    —C(O)NR⁶⁰C₁₋₄alkyl-, (wherein R⁵⁹ and R⁶⁰, which may be the same or    different, each represents hydrogen, C₁₋₃alkyl, C₁₋₃hydroxyalkyl or    C₁₋₃alkoxyC₂₋₃alkyl));-   6) (C₁₋₇alkyl)_(c)Y⁹Z³ (wherein c is 0 or 1, Z³ is an amino acid    group and Y⁹ is a direct bond, —C(O)— or —NR⁶¹— (wherein R⁶¹ is    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and-   7) C₁₋₇alkylR¹⁵ (wherein R¹⁵ is as defined hereinbefore));-   and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl or    cycloalkyl group may bear one or more substituents selected from    C₁₋₄alkoxy and phenyl).-   Advantageously X is —CH(R⁷)— wherein R⁷ is —OR⁸ or —NR⁸R⁹ (wherein    R⁸ is a group —Y¹R¹⁰ (wherein Y¹ is —C(O)—, —C(O)O— or —C(O)NR¹¹—    (wherein R¹¹ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)    and R¹⁰ is as defined hereinbefore) and R⁹ is as defined    hereinbefore).-   Preferably X is —CH(R⁷)— wherein R⁷ is —OR⁸ or —NR⁸R⁹ (wherein R⁸ is    a group —Y¹R¹⁰ (wherein Y¹ is —C(O)— or —C(O)O— and R¹⁰ is as    defined hereinbefore) and R⁹ is as defined hereinbefore).-   In one embodiment of the present invention preferably X is —C(O)—,    —CH₂—, —CH(OH)— or —CH(NHC(O)CH₃)—.-   In one embodiment of the present invention more preferably X is    —CH(NHC(O)CH₃)—.-   Conveniently R¹, R² and R³ are each independently hydrogen, PO₃H₂,    sulphate, C₁₋₇alkyl, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,    C₁₋₇alkanoyl, C₁₋₇alkylsulphonyl or a group R²⁰C₁₋₇alkyl (wherein    R²⁰ is phenyl which may bear one or more substituents selected from    C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄aminoalkyl and C₁₋₄hydroxyalkoxy); with    the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl.-   Preferably R¹, R² and R³ are each independently C₁₋₄alkyl.-   More preferably R¹, R² and R³ are each methyl.-   Conveniently R⁴ is hydrogen, cyano, halogeno, nitro, amino, hydroxy,    C₁₋₇alkoxy, C₁₋₇thioalkoxy, C₁₋₇alkanoyl or C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, nitro,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))).-   Preferably R⁴ is hydrogen, hydroxy, halogeno, cyano, amino or    C₁₋₇alkanoyl.-   More preferably R⁴ is hydrogen.-   Conveniently R⁵ and R⁶ are each independently selected from:-   hydrogen, —OPO₃H₂, phosphonate, cyano, halogeno, nitro, amino,    carboxy, carbamoyl, hydroxy, C₁₋₇alkoxy, C₁₋₇alkanoyl,    C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))); and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —C₁₋₄alkylNR³⁶—, —C₁₋₄alkylC(O)—, —NR³⁷C(O)—, —OC(O)O—,        —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein R³⁶, R³⁷, R³⁸ and R³⁹, which        may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    -   R³⁵ is a sugar moiety, a mono-peptide, a di-peptide, a        tri-peptide, a tetra-peptide, sulphate, hydroxy, amino,        C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇alkylamino,        di(C₁₋₇alkyl)amino, aminoC₁₋₇alkylamino,        C₁₋₇alkylaminoC₁₋₇alkylamino, C₁₋₇alkanoylaminoC₁₋₇alkyl,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate,        C₁₋₇alkylphosphonate, C₁₋₇alkylcarbamoylC₁₋₇alkyl,        -   (which alkyl, alkoxy, alkanoyl, alkylamino, dialkylamino,            aminoalkylamino, alkylaminoalkylamino, alkanoylaminoalkyl,            dialkylaminoalkylamino, alkylphosphate, alkylphosphonate or            alkylcarbamoylalkyl, may bear one or more substituents            selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            carboxy, phenyl, nitro, sulphate, phosphate and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or            —O—C(O)— (wherein R⁴¹ and R⁴² which may be the same or            different each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is C₁₋₇alkyl, C₃₋₇cycloalkyl,            carboxyC₁₋₇alkyl or a group R⁴³ wherein R⁴³ is a phenyl            group, a benzyl group or a 5–10-membered aromatic            heterocyclic group (linked via carbon or nitrogen) with 1–4            heteroatoms selected independently from O, N and S, which            phenyl, benzyl or aromatic heterocyclic group may bear one            or more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷            (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from        -   hydroxy, nitro, halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl,            di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,            di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy,            carboxy, C₁₋₄carboxyalkyl, phenyl, cyano, —CONR⁴⁹R⁵⁰,            —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the            same or different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (wherein R⁵³ is as            defined hereinafter),    -   C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as defined hereinbefore),    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from        -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,            C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴ (wherein R⁵⁴ is a            5–6-membered saturated heterocyclic group (linked via carbon            or nitrogen) with 1–2 heteroatoms, selected independently            from O, S and N, which heterocyclic group may bear 1 or 2            substituents selected from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and                C₁₋₄alkylsulphonylC₁₋₄alkyl)), or    -   (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³ (wherein R⁵³ is as defined hereinbefore,        a is 0, or an integer 1–4, b is 0 or an integer 1–4 and Y⁶        represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or        —C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl), and wherein one or more of the (CH₂)_(a)        or (CH₂)_(b) groups may bear one or more substituents selected        from hydroxy, amino and halogeno));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy    (wherein R⁵ is Y⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one    or more substituents selected from the list given hereinbefore),    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy.-   In another embodiment of the present invention conveniently R⁵ and    R⁶ are each independently selected from:-   hydrogen, —OPO₃H₂, cyano, halogeno, nitro, amino, carboxy, hydroxy,    C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))), and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —NR³⁷C(O)—, —OC(O)O—, —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein        R³⁶, R³⁷, R³⁸ and R³⁹, which may be the same or different, each        represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁵        is a sugar moiety, a mono-peptide, a di-peptide, a tri-peptide,        a tetra-peptide, sulphate, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl,        aminoC₁₋₇alkylamino, C₁₋₇alkylaminoC₁₋₇alkylamino,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate        -   (which alkyl, alkoxy, alkanoyl, aminoalkylamino,            alkylaminoalkylamino, dialkylaminoalkylamino, or            alkylphosphate may bear one or more substituents selected            from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,            C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,            nitro, sulphate, phosphate and a group —Y⁵R⁴⁰ (wherein Y⁵ is            —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or —O—C(O)— (wherein R⁴¹            and R⁴² which may be the same or different each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is            C₁₋₇alkyl, C₃₋₇cycloalkyl, carboxyC₁₋₇alkyl or a group R⁴³            wherein R⁴³ is a phenyl group, a benzyl group or a            5–10-membered aromatic heterocyclic group (linked via carbon            or nitrogen) with 1–4 heteroatoms selected independently            from O, N and S, which phenyl, benzyl or aromatic            heterocyclic group may bear one or more substituents            selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,            C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano,            —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷ (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷,            which may be the same or different, each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, phenyl, cyano, —CONR⁴⁹R⁵⁰ and        —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the same        or different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)), or    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,        C₁₋₄alkylsulphonylC₁₋₄alkyl and    -   R⁵⁴ (wherein R⁵⁴ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and        C₁₋₄alkylsulphonylC₁₋₄alkyl)));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy,    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy.-   Preferably R⁶ is hydrogen, halogeno, amino, carboxy, hydroxy,    C₁₋₇alkoxy or a group Y⁴R³⁵ (wherein Y⁴ is —C(O)—, —O— or —OSO₂— and    R³⁵ is C₁₋₇alkyl, C₁₋₇alkoxy (which alkyl or alkoxy may bear one or    more substituents selected from halogeno), R⁴⁸ (wherein R⁴⁸ is a    benzyl group) or R⁵³ (wherein R⁵³ is a 5–6-membered saturated    heterocyclic group (linked via carbon or nitrogen) with 1–2    heteroatoms selected independently from O, S and N)).-   Particularly R⁶ is hydrogen, C(O)OCH₃ or methoxy, especially    C(O)OCH₃ or methoxy.-   More preferably R⁶ is hydrogen.-   Preferably R⁵ is hydrogen, halogeno, amino, carboxy, carbamoyl,    C₁₋₇alkanoyl, C₁₋₇thioalkoxy, or-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —OSO₂—, —NR³⁶—,        —NR³⁷C(O)— or —C(O)NR³⁸— (wherein R³⁶, R³⁷ and R³⁸, which may be        the same or different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and    -   R³⁵ is a sugar moiety, a mono-peptide, a di-peptide, a        tri-peptide, a tetra-peptide, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇alkanoyl, C₁₋₇alkanoylaminoC₁₋₇alkyl,        -   (which alkyl, alkoxy, alkanoyl, alkanoylaminoalkyl may bear            one or more substituents selected from:        -   halogeno, amino, hydroxy, carboxy, and a group —Y⁵R⁴⁰            (wherein Y⁵ is —C(O)—O— or —O—C(O)— and R⁴⁰ is C₁₋₇alkyl or            a group R⁴³ wherein R⁴³ is a benzyl group),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from        -   hydroxy, fluoro, amino, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,            C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl,            di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,            di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy,            carboxy, C₁₋₄carboxyalkyl, cyano, —CONR⁴⁹R⁵⁰, —NR⁵¹COR⁵²            (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (wherein R⁵³ is as            defined hereinafter),    -   C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as defined hereinbefore),    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from        -   oxo, hydroxy, fluoro, chloro, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,            C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴ (wherein R⁵⁴ is a            5–6-membered saturated heterocyclic group (linked via carbon            or nitrogen) with 1–2 heteroatoms, selected independently            from O, S and N, which heterocyclic group may bear 1 or 2            substituents selected from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and                C₁₋₄alkylsulphonylC₁₋₄alkyl)), or    -   (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³ (wherein R⁵³ is as defined hereinbefore,        a is 0, or an integer 1–4, b is 0 or an integer 1–4 and Y⁶        represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or        —C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl), and wherein one or more of the (CH₂)_(a)        or (CH₂)_(b) groups may bear one or more substituents selected        from hydroxy, amino and halogeno));-   with the proviso that R⁵ is not alkoxy, substituted alkoxy (wherein    R⁵ is Y⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one or more    substituents selected from the list given hereinbefore),    —O—C₁₋₇alkanoyl or benzyloxy.-   Preferably R⁵³ is a group selected from morpholino, piperidinyl and    piperazinyl which group may be substituted as hereinbefore defined.-   Advantageous values for R⁵ include:-   3-{[(2R)-2,6-diaminohexanoyl]amino}propanoyloxy (such as in Example    4),-   3-[(2-aminoacetyl)amino]propanoyloxy (such as in Example 5),-   2-morpholinoacetylaminomethoxy (such as in Example 38),-   2-carboxy-3,4,5-trihydroxytetrahydro-2H-pyran-6-yloxy (such as in    Example 44),-   4-(4-methylpiperazin-1-ylmethyl)phenylcarbonyloxy (such as in    Example 16),-   4-(morpholinomethyl)phenylcarbonyloxy (such as in Example 17),-   3-(4-methylpiperazin-1-ylcarbonyl)propanoyloxy (such as in Example    40),-   5-carboxypentanoyloxy (such as in Example 41),-   3-(4-carboxyphenyl)propanoyloxy (such as in Example 18) and-   (3R)-2-amino-3-hydroxypropanoylamino (such as in Example 28).-   Another advantageous value for R⁵ is-   (2S)-2-amino-5-[(2-nitroethanimidoyl)amino]pentanoylamino (such as    in Example 52).-   Preferred values for R⁵ include-   3-{[(2R)-2,6-diaminohexanoyl]amino}propanoyloxy (such as in Example    4),-   3-[(2-aminoacetyl)amino]propanoyloxy (such as in Example 5),-   4-(4-methylpiperazin-1-ylmethyl)phenylcarbonyloxy (such as in    Example 16),-   4-(morpholinomethyl)phenylcarbonyloxy (such as in Example 17),-   3-(4-methylpiperazin-1-ylcarbonyl)propanoyloxy (such as in Example    40),-   5-carboxypentanoyloxy (such as in Example 41),-   3-(4-carboxyphenyl)propanoyloxy (such as in Example 18) and-   (3R)-2-amino-3-hydroxypropanoylamino (such as in Example 28).-   More preferred values for R⁵ include-   4-(4-methylpiperazin-1-ylmethyl)phenylcarbonyloxy (such as in    Example 16) and-   (3R)-2-amino-3-hydroxypropanoylamino (such as in Example 28).-   In another embodiment of the present invention preferred values for    R⁵ include alanylamino, N-(benzyloxycarbonylalanyl)amino, and    4-(piperidino)piperidin-1-ylcarbonyloxy.-   A more preferred value for R⁵ is alanylamino.-   In another embodiment of the present invention particular values of    R⁵ include amino, C₁₋₇alkylamino and diC₁₋₇alkylamino, especially    amino.-   When R³⁵ is a sugar moiety it can be, for example a monosaccharide    such as a glucuronyl, glucosyl or galactosyl group or a di- or    trisaccharide.-   When R³⁵ is a sugar moiety glucuronyl or a derivative thereof is    preferred.-   When R³⁵ is a mono-, di-, tri- or tetra-peptide it is preferably    derived from a natural alpha amino acid for example such as glycine,    valine, lysine, alanine or serine.-   In another embodiment of the present invention R³⁵ is an amino acid    group derived from serine, threonine, arginine, glycine, alanine,    β-alanine or lysine.

According to another aspect of the present invention there is providedthe use of a compound of the formula I:

wherein

-   X is —C(O)—, —C(S)—, —C═NOH, or —CH(R⁷)— wherein R⁷ is hydrogen,    hydroxy, C₁₋₇alkoxy, —NR⁸R⁹ (wherein R⁸ is a group —Y¹R¹⁰ (wherein    Y¹ is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O—, —C(O)NR¹¹—, —SO₂—    or —SO₂NR¹²— (wherein R¹¹ and R¹², which may be the same or    different, each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ is selected from one of the following    four groups:-   1) hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl    -   (which alkyl or cycloalkyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        phenyl, nitro, sulphate, phosphate and a group —Y²R¹³ (wherein        Y² is —NR¹⁴C(O)— or —O—C(O)— (wherein R¹⁴ represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is C₁₋₇alkyl,        C₃₋₇cycloalkyl or a group R¹⁵ wherein R¹⁵ is a phenyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl or aromatic heterocyclic group may bear one        or more substituents selected from hydroxy, nitro, halogeno,        amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR¹⁶R¹⁷ and —NR¹⁸COR¹⁹ (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)));-   2) R¹⁵ wherein R¹⁵ is as defined hereinbefore;-   3) C₂₋₇alkenylR¹⁵ (wherein R¹⁵ is as defined hereinbefore); and-   4) C₃₋₇alkynylR¹⁵ (wherein R¹⁵ is as defined hereinbefore));-   and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl or    cycloalkyl group may bear one or more substituents selected from    C₁₋₄alkoxy and phenyl);-   R¹, R² and R³ are each independently-   hydrogen, PO₃H₂, sulphate, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,    C₁₋₇alkanoyl, a group R²⁰C₁₋₇alkyl (wherein R²⁰ is phenyl which may    bear one or more substituents selected from C₁₋₄alkyl, C₁₋₄alkoxy,    C₁₋₄aminoalkyl and C₁₋₄hydroxyalkoxy), C₁₋₇alkyl or    C₁₋₇alkylsulphonyl    -   (which alkyl or alkylsulphonyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        carboxy, phenyl, nitro, sulphate, phosphate and a group —Y²R²¹        (wherein Y² is —NR²²C(O)— or —O—C(O)— (wherein R²² represents        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is        C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R²³ wherein R²³ is a phenyl        group or a 5–10-membered aromatic heterocyclic group (linked via        carbon or nitrogen) with 1–4 heteroatoms selected independently        from O, N and S, which phenyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR²⁴R²⁵ and —NR²⁶COR²⁷        (wherein R²⁴, R²⁵, R²⁶ and R²⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)));-   with the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl;-   R⁴, R⁵ and R⁶ are each independently selected from:-   hydrogen, —OPO₃H₂, cyano, halogeno, nitro, amino, carboxy, hydroxy,    C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))), and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —NR³⁷C(O)—, —OC(O)O—, —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein        R³⁶, R³⁷, R³⁸ and R³⁹, which may be the same or different, each        represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    -   R³⁵ is a sugar moiety, a mono-peptide, a di-peptide, a        tri-peptide, a tetra-peptide, sulphate, C₁₋₇alkyl, C₁₋₇alkoxy,        C₁₋₇alkanoyl, aminoC₁₋₇alkylamino, C₁₋₇alkylaminoC₁₋₇alkylamino,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate        -   (which alkyl, alkoxy, alkanoyl, aminoalkylamino,            alkylaminoalkylamino, dialkylaminoalkylamino, or            alkylphosphate may bear one or more substituents selected            from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,            C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,            nitro, sulphate, phosphate and a group —Y⁵R⁴⁰ (wherein Y⁵ is            —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or —O—C(O)— (wherein R⁴¹            and R⁴² which may be the same or different each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is            C₁₋₇alkyl, C₃₋₇cycloalkyl, carboxyC₁₋₇alkyl or a group R⁴³            wherein R⁴³ is a phenyl group, a benzyl group or a            5–10-membered aromatic heterocyclic group (linked via carbon            or nitrogen) with 1–4 heteroatoms selected independently            from O, N and S, which phenyl, benzyl or aromatic            heterocyclic group may bear one or more substituents            selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,            C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano,            —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷ (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷,            which may be the same or different, each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from        -   hydroxy, nitro halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, phenyl, cyano,            —CONR⁴⁹R⁵⁰ and —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵²,            which may be the same or different, each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)), or    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from        -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl            and R⁵⁴ (wherein R⁵⁴ is a 5–6-membered saturated            heterocyclic group (linked via carbon or nitrogen) with 1–2            heteroatoms, selected independently from O, S and N, which            heterocyclic group may bear 1 or 2 substituents selected            from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and            C₁₋₄alkylsulphonylC₁₋₄alkyl)));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy,    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy;-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof for example    esters, amides and sulphides, in the manufacture of a medicament for    use in the production of a vascular damaging effect in warm-blooded    animals such as humans.

According to another aspect of the present invention there is provided acompound of the formula IIa:

wherein

-   X is —C(O)—, —C(S)—, —C═NOH, or —CH(R⁷)— wherein R⁷ is hydrogen,    hydroxy, C₁₋₇alkoxy, —OR⁸ or —NR⁸R⁹ (wherein R⁸ is a group —Y¹R¹⁰    (wherein Y¹ is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O—,    —C(O)NR¹¹—, —SO₂— or —SO₂NR¹²— (wherein R¹¹ and R¹², which may be    the same or different, each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ is selected from one of    the following nine groups:-   1) hydrogen, C₁₋₇alkyl, C₃₋₇cycloalkyl, C₁₋₄alkylY⁸C₁₋₄alkyl wherein    Y⁸ is as defined hereinafter, or phenyl,    -   (which alkyl, cycloalkyl, alkylY⁸alkyl or phenyl group may bear        one or more substituents selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, carboxy, carbamoyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            phenyl, nitro, sulphate, phosphate,        -   Z¹ (wherein Z¹ represents a 5–6 membered saturated            heterocyclic group (linked via carbon or nitrogen) with 1–2            heteroatoms, selected independently from O, S and N, which            heterocyclic group may bear 1 or 2 substituents selected            from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,                C₁₋₄alkylsulphonylC₁₋₄alkyl and Z² (wherein Z² is a                5–6-membered saturated heterocyclic group (linked via                carbon or nitrogen) with 1–2 heteroatoms, selected                independently from O, S and N, which heterocyclic group                may bear 1 or 2 substituents selected from                -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                    C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₄alkanoyl,                    cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl and                    C₁₋₄alkylsulphonylC₁₋₄alkyl)),        -   C₁₋₄alkylZ¹ (wherein Z¹ is as defined hereinbefore), and        -   a group —Y²R¹³ (wherein Y² is —NR¹⁴C(O)— or —O—C(O)—            (wherein R¹⁴ represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is C₁₋₇alkyl, C₃₋₇cycloalkyl or            a group R¹⁵ wherein R¹⁵ is a phenyl group or a 5–10-membered            aromatic heterocyclic group (linked via carbon or nitrogen)            with 1–4 heteroatoms selected independently from O, N and S,            which phenyl or aromatic heterocyclic group may bear one or            more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR¹⁶R¹⁷ and —NR¹⁸COR¹⁹            (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl)));-   2) R¹⁵ wherein R¹⁵ is as defined hereinbefore;-   3) C₂₋₇alkenylR¹⁵ (wherein R¹⁵ is as defined hereinbefore);-   4) C₃₋₇alkynylR¹⁵ (wherein R¹⁵ is as defined hereinbefore));-   5) Z¹ (wherein Z¹ is as defined hereinbefore);-   6) C₁₋₇alkylZ¹ (wherein Z¹ is as defined hereinbefore);-   7) C₁₋₇alkylY⁸Z¹ (wherein Z¹ is as defined hereinbefore and Y⁸ is    —C(O)—, —NR⁵⁹C(O)—, —NR⁵⁹C(O)C₁₋₄alkyl-, —C(O)NR⁶⁰— or    —C(O)NR⁶⁰C₁₋₄alkyl-, (wherein R⁵⁹ and R⁶⁰, which may be the same or    different, each represents hydrogen, C₁₋₃alkyl, C₁₋₃hydroxyalkyl or    C₁₋₃alkoxyC₂₋₃alkyl));-   8) (C₁₋₇alkyl)_(c)Y⁹Z³ (wherein c is 0 or 1, Z³ is an amino acid    group and Y⁹ is a direct bond, —C(O)— or —NR⁶¹— (wherein R⁶¹ is    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and-   9) C₁₋₇alkylR¹⁵ (wherein R¹⁵ is as defined hereinbefore);-   and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl or    cycloalkyl group may bear one or more substituents selected from    C₁₋₄alkoxy and phenyl);-   R¹, R² and R³ are each independently-   hydrogen, PO₃H₂, sulphate, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,    C₁₋₇alkanoyl, a group R²⁰C₁₋₇alkyl (wherein R²⁰ is phenyl which may    bear one or more substituents selected from C₁₋₄alkyl, C₁₋₄alkoxy,    C₁₋₄aminoalkyl and C₁₋₄hydroxyalkoxy), C₁₋₇alkyl or    C₁₋₇alkylsulphonyl    -   (which alkyl or alkylsulphonyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        carboxy, phenyl, nitro, sulphate, phosphate and a group —Y²R²¹        (wherein Y² is —NR²²C(O)— or —O—C(O)— (wherein R²² represents        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is        C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R²³ wherein R²³ is a phenyl        group or a 5–10-membered aromatic heterocyclic group (linked via        carbon or nitrogen) with 1–4 heteroatoms selected independently        from O, N and S, which phenyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR²⁴R²⁵ and —NR²⁶COR²⁷        (wherein R²⁴, R²⁵, R²⁶ and R²⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)));-   with the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl;-   R⁴ is hydrogen, cyano, halogeno, nitro, amino, hydroxy, C₁₋₇alkoxy,    C₁₋₇thioalkoxy, C₁₋₇alkanoyl or C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, nitro,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)));-   R⁵ and R⁶ are each independently selected from-   hydrogen, —OPO₃H₂, phosphonate, cyano; halogeno, nitro, amino,    carboxy, carbamoyl, hydroxy, C₁₋₇alkoxy, C₁₋₇alkanoyl,    C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))), and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —C₁₋₄alkylNR³⁶—, —C₁₋₄alkylC(O)—, —NR³⁷C(O)—, —OC(O)O—,        —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein R³⁶, R³⁷, R³⁸ and R³⁹, which        may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    -   R³⁵ is a sugar moiety, a mono-peptide, a di-peptide, a        tri-peptide, a tetra-peptide, sulphate, hydroxy, amino,        C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇alkylamino,        di(C₁₋₇alkyl)amino, aminoC₁₋₇alkylamino,        C₁₋₇alkylaminoC₁₋₇alkylamino, C₁₋₇alkanoylaminoC₁₋₇alkyl,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate,        C₁₋₇alkylphosphonate, C₁₋₇alkylcarbamoylC₁₋₇alkyl,        -   (which alkyl, alkoxy, alkanoyl, alkylamino, dialkylamino,            aminoalkylamino, alkylaminoalkylamino, alkanoylaminoalkyl,            dialkylaminoalkylamino, alkylphosphate, alkylphosphonate or            alkylcarbamoylalkyl, may bear one or more substituents            selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            carboxy, phenyl, nitro, sulphate, phosphate and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or            —O—C(O)— (wherein R⁴¹ and R⁴² which may be the same or            different each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is C₁₋₇alkyl, C₃₋₇cycloalkyl,            carboxyC₁₋₇alkyl or a group R⁴³ wherein R⁴³ is a phenyl            group, a benzyl group or a 5–10-membered aromatic            heterocyclic group (linked via carbon or nitrogen) with 1–4            heteroatoms selected independently from O, N and S, which            phenyl, benzyl or aromatic heterocyclic group may bear one            or more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷            (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from        -   hydroxy, nitro, halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl,            di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,            di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy,            carboxy, C₁₋₄carboxyalkyl, phenyl, cyano, —CONR⁴⁹R⁵⁰,            —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the            same or different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (wherein R⁵³ is as            defined hereinafter),    -   C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as defined hereinbefore),    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from        -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,            C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴ (wherein R⁵⁴ is a            5–6-membered saturated heterocyclic group (linked via carbon            or nitrogen) with 1–2 heteroatoms, selected independently            from O, S and N, which heterocyclic group may bear 1 or 2            substituents selected from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and                C₁₋₄alkylsulphonylC₁₋₄alkyl)), or    -   (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³ (wherein R⁵³ is as defined hereinbefore,        a is 0, or an integer 1–4, b is 0 or an integer 1–4 and Y⁶        represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or        —C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl), and wherein one or more of the (CH₂)_(a)        or (CH₂)_(b) groups may bear one or more substituents selected        from hydroxy, amino and halogeno));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy    (wherein R⁵ is Y⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one    or more substituents selected from the list given hereinbefore),    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy;-   with the further proviso that at least one of R⁵ or R⁶ is a group    —Y⁴R³⁵ (wherein Y⁴ and R³⁵ are as defined hereinbefore) but with the    further provisos that when R⁵ is —Y⁴R³⁵ and R⁶ is hydrogen, hydroxy,    methoxy or methoxycarbonyl, —Y⁴R³⁵ is not selected from cases    wherein:    -   Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —OSO₂—, —NR³⁶—, —NR³⁷C(O)— or        —C(O)NR³⁸— (wherein R³⁶, R³⁷ and R³⁸, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁵ is    -   a glycine, valine or lysine group, a dipeptide of glycine and        valine groups, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl,        -   (which alkyl, alkoxy or alkanoyl may bear one or more            substituents selected from: halogeno, hydroxy, and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —O—C(O)— and R⁴⁰ is C₁₋₇alkyl)), or    -   R⁴⁸ (wherein R⁴⁸ is a tetrazolyl group (which may or may not be        substituted as hereinbefore defined), a phenyl group or a benzyl        group which phenyl or benzyl group may bear one or more        substituents selected from C₁₋₄alkyl); and-   that when R⁶ is —Y⁴R³⁵ and R⁵ is hydrogen, hydroxy, methoxy or    methoxycarbonyl, —Y⁴R³⁵ is not selected from cases wherein:    -   Y⁴ is —C(O)—, —O— or —OSO₂— and R³⁵ is    -   C₁₋₇alkyl, C₁₋₇alkoxy        -   (which alkyl, alkoxy or alkanoyl may bear one or more            substituents selected from: halogeno),    -   R⁴⁸ (wherein R⁴⁸ is a benzyl group which benzyl group may bear        one or more substituents selected from C₁₋₄alkyl), or    -   R⁵³ (wherein R⁵³ is piperidinyl);-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof.

According to a further aspect of the present invention there is provideda compound of the formula IIa:

wherein

-   X is —C(O)—, —C(S)—, —C═NOH, or —CH(R⁷)— wherein R⁷ is hydrogen,    hydroxy, C₁₋₇alkoxy, —OR⁸ or —NR⁸R⁹ (wherein R⁸ is a group —Y¹R¹⁰    (wherein Y¹ is a direct bond, —C(O)—, —C(S)—, —S—, —C(O)O—,    —C(O)NR¹¹—, —SO₂— or —SO₂NR¹²— (wherein R¹¹ and R¹², which may be    the same or different, each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ is selected from one of    the following nine groups:-   1) hydrogen, C₁₋₇alkyl, C₃₋₇cycloalkyl, C₁₋₄alkylY⁸C₁₋₄alkyl wherein    Y⁸ is as defined hereinafter, or phenyl,    -   (which alkyl, cycloalkyl, alkylY⁸alkyl or phenyl group may bear        one or more substituents selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, carboxy, carbamoyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            phenyl, nitro, sulphate, phosphate,        -   Z¹ (wherein Z¹ represents a 5–6 membered saturated            heterocyclic group (linked via carbon or nitrogen) with 1–2            heteroatoms, selected independently from O, S and N, which            heterocyclic group may bear 1 or 2 substituents selected            from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,                C₁₋₄alkylsulphonylC₁₋₄alkyl and Z² (wherein Z² is a                5–6-membered saturated heterocyclic group (linked via                carbon or nitrogen) with 1–2 heteroatoms, selected                independently from O, S and N, which etherocyclic group                may bear 1 or 2 substituents selected from                -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                    C₁₋₄alkoxy, C₁₋₄aminoalkyl, C₁₋₇alkanoyl,                    cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl and                    C₁₋₄alkylsulphonylC₁₋₄alkyl)),        -   C₁₋₄alkylZ¹ (wherein Z¹ is as defined hereinbefore), and        -   a group —Y²R¹³ (wherein Y² is —NR¹⁴C(O)— or —O—C(O)—            (wherein R¹⁴ represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is C₁₋₇alkyl, C₃₋₇cycloalkyl or            a group R¹⁵ wherein R¹⁵ is a phenyl group or a 5–10-membered            aromatic heterocyclic group (linked via carbon or nitrogen)            with 1–4 heteroatoms selected independently from O, N and S,            which phenyl or aromatic heterocyclic group may bear one or            more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR¹⁶R¹⁷ and —NR¹⁸COR¹⁹            (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl)));-   2) R¹⁵ wherein R¹⁵ is as defined hereinbefore;-   3) C₂₋₇alkenylR¹⁵ (wherein R¹⁵ is as defined hereinbefore);-   4) C₃₋₇alkynylR¹⁵ (wherein R¹⁵ is as defined hereinbefore));-   5) Z¹ (wherein Z¹ is as defined hereinbefore);-   6) C₁₋₇alkylZ¹ (wherein Z¹ is as defined hereinbefore);-   7) C₁₋₇alkylY⁸Z¹ (wherein Z¹ is as defined hereinbefore and Y⁸ is    —C(O)—, —NR⁵⁹C(O)—, —NR⁵⁹C(O)C₁₋₄alkyl-, —C(O)NR⁶⁰— or    —C(O)NR⁶⁰C₁₋₄alkyl-, (wherein R⁵⁹ and R⁶⁰, which may be the same or    different, each represents hydrogen, C₁₋₃alkyl, C₁₋₃hydroxyalkyl or    C₁₋₃alkoxyC₂₋₃alkyl));-   8) (C₁₋₇alkyl)_(c)Y⁹Z³ (wherein c is 0 or 1, Z³ is an amino acid    group and Y⁹ is a direct bond, —C(O)— or —NR⁶¹— (wherein R⁶¹ is    hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); and-   9) C₁₋₇alkylR¹⁵ (wherein R¹⁵ is as defined hereinbefore);-   and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl or    cycloalkyl group may bear one or more substituents selected from    C₁₋₄alkoxy and phenyl);-   R¹, R² and R³ are each independently-   hydrogen, PO₃H₂, sulphate, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,    C₁₋₇alkanoyl, a group R²⁰C₁₋₇alkyl (wherein R²⁰ is phenyl which may    bear one or more substituents selected from C₁₋₄alkyl, C₁₋₄alkoxy,    C₁₋₄aminoalkyl and C₁₋₄hydroxyalkoxy), C₁₋₇alkyl or    C₁₋₇alkylsulphonyl    -   (which alkyl or alkylsulphonyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        carboxy, phenyl, nitro, sulphate, phosphate and a group —Y²R²¹        (wherein Y² is —NR²²C(O)— or —O—C(O)— (wherein R²² represents        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is        C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R²³ wherein R²³ is a phenyl        group or a 5–10-membered aromatic heterocyclic group (linked via        carbon or nitrogen) with 1–4 heteroatoms selected independently        from O, N and S, which phenyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR²⁴R²⁵ and —NR²⁶COR²⁷        (wherein R²⁴, R²⁵, R²⁶ and R²⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)));-   with the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl;-   R⁴ is hydrogen, cyano, halogeno, nitro, amino, hydroxy, C₁₋₇alkoxy,    C₁₋₇thioalkoxy, C₁₋₇alkanoyl or C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, nitro,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)));-   R⁵ and R⁶ are each independently selected from-   hydrogen, —OPO₃H₂, phosphonate, cyano, halogeno, nitro, amino,    carboxy, carbamoyl, hydroxy, C₁₋₇alkoxy, C₁₋₇alkanoyl,    C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))), and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —C₁₋₄alkylNR³⁶—, —C₁₋₄alkylC(O)—, —NR³⁷C(O)—, —OC(O)O—,        —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein R³⁶, R³⁷, R³⁸ and R³⁹, which        may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    -   R³⁵ is a sugar moiety, a mono-peptide, a di-peptide, a        tri-peptide, a tetra-peptide, sulphate, hydroxy, amino,        C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇alkylamino,        di(C₁₋₇alkyl)amino, aminoC₁₋₇alkylamino,        C₁₋₇alkylaminoC₁₋₇alkylamino, C₁₋₇alkanoylaminoC₁₋₇alkyl,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate,        C₁₋₇alkylphosphonate, C₁₋₇alkylcarbamoylC₁₋₇alkyl,        -   (which alkyl, alkoxy, alkanoyl, alkylamino, dialkylamino,            aminoalkylamino, alkylaminoalkylamino, alkanoylaminoalkyl,            dialkylaminoalkylamino, alkylphosphate, alkylphosphonate or            alkylcarbamoylalkyl, may bear one or more substituents            selected from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,            C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,            carboxy, phenyl, nitro, sulphate, phosphate and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or            —O—C(O)— (wherein R⁴¹ and R⁴² which may be the same or            different each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is C₁₋₇alkyl, C₃₋₇cycloalkyl,            carboxyC₁₋₇alkyl or a group R⁴³ wherein R⁴³ is a phenyl            group, a benzyl group or a 5–10-membered aromatic            heterocyclic group (linked via carbon or nitrogen) with 1–4            heteroatoms selected independently from O, N and S, which            phenyl, benzyl or aromatic heterocyclic group may bear one            or more substituents selected from hydroxy, nitro, halogeno,            amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,            C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,            C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷            (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷, which may be the same or            different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from        -   hydroxy, nitro, halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl,            C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl,            di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,            di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy,            carboxy, C₁₋₄carboxyalkyl, phenyl, cyano, —CONR⁴⁹R⁵⁰,            —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the            same or different, each represents hydrogen, C₁₋₃alkyl or            C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (wherein R⁵³ is as            defined hereinafter),    -   C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as defined hereinbefore),    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from        -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,            C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,            di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,            C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴ (wherein R⁵⁴ is a            5–6-membered saturated heterocyclic group (linked via carbon            or nitrogen) with 1–2 heteroatoms, selected independently            from O, S and N, which heterocyclic group may bear 1 or 2            substituents selected from            -   oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,                C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and                C₁₋₄alkylsulphonylC₁₋₄alkyl)), or    -   (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³ (wherein R⁵³ is as defined hereinbefore,        a is 0, or an integer 1–4, b is 0 or an integer 1–4 and Y⁶        represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or        —C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl), and wherein one or more of the (CH₂)_(a)        or (CH₂)_(b) groups may bear one or more substituents selected        from hydroxy, amino and halogeno));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy    (wherein R⁵ is Y⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one    or more substituents selected from the list given hereinbefore),    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy;-   with the further proviso that at least one of R⁵ or R⁶ is a group    —Y⁴R³⁵ (wherein Y⁴ and R³⁵ are as defined hereinbefore) but with the    further provisos that when R⁵ is —Y⁴R³⁵ and R⁶ is hydrogen, hydroxy,    methoxy or methoxycarbonyl, —Y⁴R³⁵ is not selected from cases    wherein:    -   Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —OSO₂—, —NR³⁶—, —NR³⁷C(O)— or        —C(O)NR³⁸— (wherein R³⁶, R³⁷ and R³⁸, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁵ is    -   a mono-peptide, a di-peptide, a tri-peptide, a tetra-peptide,        C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl,        -   (which alkyl, alkoxy or alkanoyl may bear one or more            substituents selected from: halogeno, hydroxy, and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —O—C(O)— and R⁴⁰ is C₁₋₇alkyl)), or    -   R⁴⁸ (wherein R⁴⁸ is a tetrazolyl group (which may or may not be        substituted as hereinbefore defined), a phenyl group or a benzyl        group which phenyl or benzyl group may bear one or more        substituents selected from C₁₋₄alkyl); and-   that when R⁶ is —Y⁴R³⁵ and R⁵ is hydrogen, hydroxy, methoxy or    methoxycarbonyl, —Y⁴R³⁵ is not selected from cases wherein:    -   Y⁴ is —C(O)—, —O— or —OSO₂— and R³⁵ is    -   C₁₋₇alkyl, C₁₋₇alkoxy        -   (which alkyl, alkoxy or alkanoyl may bear one or more            substituents selected from: halogeno),    -   R⁴⁸ (wherein R⁴⁸ is a benzyl group which benzyl group may bear        one or more substituents selected from C₁₋₄alkyl), or    -   R⁵³ (wherein R⁵³ is piperidinyl);-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof.

According to a further aspect of the present invention there is providedthe use of a compound of the formula IIa as defined hereinbefore, andsalts thereof, pharmaceutically acceptable salts thereof, solvates andhydrates thereof, and prodrugs thereof, in the manufacture of amedicament for use in the production of a vascular damaging effect inwarm-blooded animals such as humans.

According to another aspect of the present invention there is providedthe use of a compound of the formula IIb:

wherein

-   X is —C(O)—, —C(S)—, or —CH(R⁷)— wherein R⁷ is hydrogen, hydroxy or    —NR⁸R⁹ (wherein R⁸ is a group —Y¹R¹⁰ (wherein Y¹ is a direct bond,    —C(O)—, —C(S)—, —C(O)O—, —C(O)NR¹¹—, —SO₂— or —SO₂NR¹²— (wherein R¹¹    and R¹², which may be the same or different, each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ is    selected from one of the following two groups:-   1) hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl    -   (which alkyl or cycloalkyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        phenyl, nitro, sulphate, phosphate and a group —Y²R¹³ (wherein        Y² is —NR¹⁴C(O)— or —O—C(O)— (wherein R¹⁴ represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹³ is C₁₋₇alkyl,        C₃₋₇cycloalkyl or a group R¹⁵ wherein R¹⁵ is a phenyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl or aromatic heterocyclic group may bear one        or more substituents selected from hydroxy, nitro, halogeno,        amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR¹⁶R¹⁷ and —NR¹⁸COR¹⁹ (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))); and-   2) R¹⁵ wherein R¹⁵ is as defined hereinbefore;-   and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl or    cycloalkyl group may bear one or more substituents selected from    C₁₋₄alkoxy and phenyl);-   R¹, R² and R³ are each independently-   hydrogen, PO₃H₂, sulphate, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl,    C₁₋₇alkanoyl, a group R²⁰C₁₋₇alkyl (wherein R²⁰ is phenyl which may    bear one or more substituents selected from C₁₋₄alkyl, C₁₋₄alkoxy,    C₁₋₄aminoalkyl and C₁₋₄hydroxyalkoxy), C₁₋₇alkyl or    C₁₋₇alkylsulphonyl    -   (which alkyl or alkylsulphonyl group may bear one or more        substituents selected from: halogeno, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,        C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl,        carboxy, phenyl, nitro, sulphate, phosphate and a group —Y²R²¹        (wherein Y² is —NR²²C(O)— or —O—C(O)— (wherein R²² represents        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is        C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R²³ wherein R²³ is a phenyl        group or a 5–10-membered aromatic heterocyclic group (linked via        carbon or nitrogen) with 1–4 heteroatoms selected independently        from O, N and S, which phenyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR²⁴R²⁵ and —NR²⁶COR²⁷        (wherein R²⁴, R²⁵, R²⁶ and R²⁷, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)));-   with the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl;-   R⁴ is hydrogen, cyano, halogeno, nitro, amino, hydroxy, C₁₋₇alkoxy,    C₁₋₇thioalkoxy, C₁₋₇alkanoyl or C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from:    -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, hydroxy,        C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, nitro,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)));-   R⁵ and R⁶ are each independently selected from-   hydrogen, —OPO₃H₂, cyano, halogeno, nitro, amino, carboxy, hydroxy,    C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇thioalkoxy, C₁₋₇alkyl,    -   (which alkyl group may bear one or more substituents selected        from: halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,        hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,        C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,        sulphate, phosphate and a group —Y³R²⁸ (wherein Y³ is —NR²⁹C(O)—        or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a        group R³⁰ wherein R³⁰ is a phenyl group or a 5–10-membered        aromatic heterocyclic group (linked via carbon or nitrogen) with        1–4 heteroatoms selected independently from O, N and S, which        phenyl or aromatic heterocyclic group may bear one or more        substituents selected from hydroxy, nitro, halogeno, amino,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,        C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,        cyano, —CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴,        which may be the same or different, each represents hydrogen,        C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))), and-   a group —Y⁴R³⁵    -   (wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—, —OSO₂—,        —NR³⁶—, —NR³⁷C(O)—, —OC(O)O—, —C(O)NR³⁸— or —NR³⁹C(O)O— (wherein        R³⁶, R³⁷, R³⁸ and R³⁹, which may be the same or different, each        represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁵        is a sugar moiety, a mono-peptide, a di-peptide, a tri-peptide,        a tetra-peptide, sulphate, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl,        aminoC₁₋₇alkylamino, C₁₋₇alkylaminoC₁₋₇alkylamino,        di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, C₁₋₇alkylphosphate        -   (which alkyl, alkoxy, alkanoyl, aminoalkylamino,            alkylaminoalkylamino, dialkylaminoalkylamino, or            alkylphosphate may bear one or more substituents selected            from:        -   halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,            hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,            C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl,            nitro, sulphate, phosphate and a group —Y⁵R⁴⁰ (wherein Y⁵ is            —NR⁴¹C(O)—, —C(O)NR⁴²—, —C(O)—O— or —O—C(O)— (wherein R⁴¹            and R⁴² which may be the same or different each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁴⁰ is            C₁₋₇alkyl, C₃₋₇cycloalkyl, carboxyC₁₋₇alkyl or a group R⁴³            wherein R⁴³ is a phenyl group, a benzyl group or a            5–10-membered aromatic heterocyclic group (linked via carbon            or nitrogen) with 1–4 heteroatoms selected independently            from O, N and S, which phenyl, benzyl or aromatic            heterocyclic group may bear one or more substituents            selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,            C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,            C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano,            —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷ (wherein R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷,            which may be the same or different, each represents            hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl))),    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group, a benzyl group or a        5–10-membered aromatic heterocyclic group (linked via carbon or        nitrogen) with 1–4 heteroatoms selected independently from O, N        and S, which phenyl, benzyl or aromatic heterocyclic group may        bear one or more substituents selected from hydroxy, nitro,        halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,        C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,        C₁₋₄hydroxyalkoxy, carboxy, phenyl, cyano, —CONR⁴⁹R⁵⁰ and        —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹ and R⁵², which may be the same        or different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl)), or    -   R⁵³ (wherein R⁵³ is a 5–6-membered saturated heterocyclic group        (linked via carbon or nitrogen) with 1–2 heteroatoms, selected        independently from O, S and N, which heterocyclic group may bear        1 or 2 substituents selected from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,        C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴ (wherein R⁵⁴ is a        5–6-membered saturated heterocyclic group (linked via carbon or        nitrogen) with 1–2 heteroatoms, selected independently from O, S        and N, which heterocyclic group may bear 1 or 2 substituents        selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,        C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and        C₁₋₄alkylsulphonylC₁₋₄alkyl)));-   with the proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy,    —OPO₃H₂, —O—C₁₋₇alkanoyl or benzyloxy;-   with the further proviso that at least one of R⁵ or R⁶ is a group    —Y⁴R³⁵ (wherein Y⁴ and R³⁵ are as defined hereinbefore) but with the    further provisos-   that when R⁵ is —Y⁴R³⁵ and R⁶ is hydrogen or methoxy —Y⁴R³⁵ is not    selected from cases wherein:    -   Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —OSO₂—, —NR³⁶—, —NR³⁷C(O)— or        —C(O)NR³⁸— (wherein R³⁶, R³⁷ and R³⁸, which may be the same or        different, each represents hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁵ is    -   a mono-peptide, a di-peptide, a tri-peptide, a tetra-peptide,        C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl,        -   (which alkyl, alkoxy or alkanoyl may bear one or more            substituents selected from: halogeno, hydroxy, and a group            —Y⁵R⁴⁰ (wherein Y⁵ is —C(O)—O— or —O—C(O)— and R⁴⁰ is            C₁₋₇alkyl)), or    -   R⁴⁸ (wherein R⁴⁸ is a phenyl group or a benzyl group which        phenyl or benzyl group may bear one or more substituents        selected from C₁₋₇alkyl); and-   that when R⁶ is —Y⁴R³⁵ and R⁵ is hydrogen, hydroxy or methoxy —Y⁴R³⁵    is not selected from cases wherein:    -   Y⁴ is —C(O)—, —O— or —OSO₂— and R³⁵ is    -   C₁₋₇alkyl, C₁₋₇alkoxy        -   (which alkyl, alkoxy or alkanoyl may bear one or more            substituents selected from: halogeno),    -   R⁴⁸ (wherein R⁴⁸ is a benzyl group which phenyl or benzyl group        may bear one or more substituents selected from C₁₋₇alkyl), or    -   R⁵³ (wherein R⁵³ is piperidinyl);-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof for example    esters, amides and sulphides, in the manufacture of a medicament for    use in the production of a vascular damaging effect in warm-blooded    animals such as humans.

According to a further aspect of the present invention there is provideda compound of the formula IIb as defined hereinbefore, and saltsthereof, pharmaceutically acceptable salts thereof, solvates andhydrates thereof, and prodrugs thereof for example esters, amides andsulphides.

Preferred compounds of the present invention include:

-   (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl    3-{[(2R)-2,6-diaminohexanoyl]amino}propanoate,-   (5S)-5-(acetylamino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl    3-[(2-aminoacetyl)amino]propanoate,-   N-([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxymethyl)-2-morpholinoacetamide,-   (2S,3S,4S,5R,6R)-6-{[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy}-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic    acid,-   N-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,-   N-[(5S)-3-(4-{morpholinomethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,-   (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl    3-[4-methylpiperazin-1-ylcarbonyl]propanoate,-   5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoic    acid,-   4-(3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3-oxopropyl)benzoic    acid and-   (2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-hydroxypropanamide,-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof.    More preferred compounds of the present invention include:-   (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl    3-{[(2R)-2,6-diaminohexanoyl]amino}propanoate,-   (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl    3-[(2-aminoacetyl)amino]propanoate,-   N-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,-   N-[(5S)-3-(4-{morpholinomethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,-   (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl    3-[4-methylpiperazin-1-ylcarbonyl]propanoate,-   5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoic    acid,-   4-(3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3-oxopropyl)benzoic    acid and-   (2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-hydroxypropanamide,-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof.    Especially preferred compounds of the present invention include:-   N-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide    and-   (2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-hydroxypropanamide,-   and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof.-   In another embodiment of the present invention preferred compounds    include    (2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-5-[(2-nitroethanimidoyl)amino]pentanamide,    and salts thereof, pharmaceutically acceptable salts thereof,    solvates and hydrates thereof, and prodrugs thereof.

In one embodiment of the invention preferred compounds include those inwhich R¹, R² and R³ are each alkyl, Y⁴ is NH and R³⁵ is an acyl groupderived from a natural alpha-amino acid such as glycine, L-alanine orL-serine.

In one embodiment of the invention more preferred compounds includecompounds wherein R¹, R² and R³ are each methyl, R⁴ is hydrogen and X is—CH(NHC(O)CH₃)—.

In another embodiment of the invention particular compounds includecompounds wherein R¹, R² and R³ are each alkyl and R³⁵ isaminoC₁₋₇alkylamino, C₁₋₇alkylaminoC₁₋₇alkylamino,di(C₁₋₇alkyl)aminoC₁₋₇alkylamino, 1-piperazinyl or4-(piperidino)piperidin-1-yl.

In another embodiment of the invention further particular compoundsinclude compounds wherein R¹, R² and R³ are each alkyl, R⁴ is hydrogenand X is —CH(NHC(O)CH₃)—.

In another embodiment of the invention more particular compounds includecompounds wherein R¹, R² and R³ are each alkyl and R⁴ and R⁶ are eachhydrogen.

In another embodiment of the invention especially preferred compoundsinclude compounds wherein R¹, R² and R³ are each methyl and R³⁵ is asubstituted acyl group. Preferred compounds of the present inventioninclude:

N-[3-(alanylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideand salts thereof, pharmaceutically acceptable salts thereof, solvatesand hydrates thereof, and prodrugs thereof for example esters, amidesand sulphides. A preferred compound for use in the manufacture of amedicament for use in the production of a vascular damaging effect inwarm-blooded animals such as humans isN-[3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’, or ‘hereinafter defined’ or ‘defined hereinafter’, thesaid group encompasses the first occurring and broadest definition aswell as each and all of the preferred definitions for that group.

In this specification unless stated otherwise the term “alkyl” includesboth straight and branched chain alkyl groups but references toindividual alkyl groups such as “propyl” are specific for the straightchain version only. An analogous convention applies to other genericterms. Unless otherwise stated the term “alkyl” advantageously refers tochains with 1–7 carbon atoms, preferably 1–4 carbon atoms. The term“alkoxy” as used herein, unless stated otherwise includes “alkyl”—O—groups in which “alkyl” is as hereinbefore defined. The term “aryl” asused herein unless stated otherwise includes reference to a C₆₋₁₀arylgroup which may, if desired, carry one or more substituents selectedfrom halogeno, alkyl, haloalkyl, alkoxy, hydroxy, amino, nitro andcyano, (wherein alkyl, haloalkyl and alkoxy are as hereinbefore andhereinafter defined). The term “aryloxy” as used herein unless otherwisestated includes “aryl”—O—groups in which “aryl” is as hereinbeforedefined. The term “sulphonyloxy” as used herein refers toalkylsulphonyloxy and arylsulphonyloxy groups in which “alkyl” and“aryl” are as hereinbefore defined. The term “heteroaryl” as used hereinunless stated otherwise includes reference to a C₆₋₁₀aryl groupcontaining one or more ring heteroatoms selected from O, N and S whichheteroaryl group may, if desired, carry one or more substituentsselected from halogeno, alkyl, haloalkyl, alkoxy, hydroxy, amino, nitroand cyano, (wherein alkyl, haloalkyl and alkoxy are as hereinbefore andhereinafter defined). The term “alkanoyl” as used herein unlessotherwise stated includes formyl and alkylC═O groups in which “alkyl” isas defined hereinbefore, for example C₂alkanoyl is ethanoyl and refersto CH₃C═O, C₁alkanoyl is formyl and refers to CHO. In this specificationunless stated otherwise the term “alkenyl” includes both straight andbranched chain alkenyl groups but references to individual alkenylgroups such as 2-butenyl are specific for the straight chain versiononly. Unless otherwise stated the term “alkenyl” advantageously refersto chains with 2–7 carbon atoms, preferably 2–4 carbon atoms. In thisspecification unless stated otherwise the term “alkynyl” includes bothstraight and branched chain alkynyl groups but references to individualalkynyl groups such as 2-butynyl are specific for the straight chainversion only. Unless otherwise stated the term “alkynyl” advantageouslyrefers to chains with 2–7 carbon atoms, preferably 2–4 carbon atoms. Theterm “halogeno” means fluoro, chloro, bromo or iodo unless otherwisestated. A haloalkyl group is an alkyl group as defined hereinbeforesubstituted with one or more halogeno groups for example trifluoromethyland dichloromethyl. A hydroxyalkyl group is an alkyl group as definedhereinbefore substituted with one or more hydroxy groups.

In this specification unless stated otherwise the term “acyl” refers toa group linked via a carbonyl group. “Acyl” includes a group —C(O)—R⁵⁸wherein R⁵⁸ is an alkyl, aryl or heteroaryl group as hereinbeforedefined, or —C(O)—R⁵⁸ is derived from an amino acid.

In this specification mono-peptide means an amino acid including α-aminoacids β-amino acids and γ-amino acids. The amino acids may be L-isomersor D-isomers, preferably L-isomers. Preferred amino acids includeglycine, alanine, valine, leucine, isoleucine, methionine, proline,phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine,asparaginine, glutamine, aspartic acid, glutamic acid, lysine, arginine,histidine, β-alanine and ornithine. More preferred amino acids includeserine, threonine, arginine, glycine, alanine, β-alanine and lysine.Especially preferred amino acids include serine, threonine, arginine,alanine and β-alanine.

An aromatic heterocyclic group includes those selected from pyridyl,pyrimidyl, furyl, thienyl, pyrrolyl, pyrazolyl, indolyl, benzofuryl,benzothienyl, benzothiazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, triazolyl, quinolyl and isoquinolyl.

For the avoidance of any doubt, it is to be understood that when Y¹ is,for example, a group of formula —C(O)NR¹¹—, it is the nitrogen atombearing the R¹¹ group which is attached to the group R¹⁰ and thecarbonyl group (C(O)) is attached to the nitrogen atom which is linkedto the hepten ring. A similar convention applies to the other two atomY¹ linking groups such as —SO₂NR¹²—. An analogous convention applies toother groups. It is further to be understood that when Y¹ represents—C(O)NR¹¹— and R¹¹ is C₁₋₃alkoxyC₂₋₃alkyl it is the C₂₋₃-alkyl moietywhich is linked to the nitrogen atom of Y¹ and an analogous conventionapplies to other groups.

For the avoidance of any doubt it is to be understood that when Y¹ is,for example, a group of formula —OC(O)— it is the oxygen atom which isbound to the substituted group and the carbonyl group (C(O)) which isbound to R¹³ and an analogous convention applies to other groups.

For the avoidance of any doubt it is to be understood that when Y⁴ is,for example, a group of formula —NR³⁹C(O)O— it is the nitrogen atomwhich is bound to the benz ring and the oxygen atom which is bound toR³⁵ and an analogous convention applies to other groups.

For the avoidance of any doubt it is to be understood that when R³⁵ is agroup C₁₋₇alkylR⁴⁸ it is the alkyl chain which is linked to Y⁴,similarly when R³⁵ is a group (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³ it is the(CH₂)_(a) group which is linked to Y⁴ and a similar convention appliesto other groups.

For the avoidance of any doubt, it is to be understood that when a groupcarries a C₁₋₄alkylamino substituent it is the amino moiety which isattached to the group whereas when a group carries a C₁₋₄aminoalkylsubstituent it is the C₁₋₄alkyl moiety which is attached to the groupand an analogous convention applies to other substituents.

Within the present invention it is to be understood that a compound ofthe formula I or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form which hasvascular damaging activity and is not to be limited merely to any onetautomeric form utilised within the formulae drawings. The formulaedrawings within this specification can represent only one of thepossible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein.

It will be appreciated that compounds of the formula I or a salt thereofmay possess an asymmetric carbon atom. Such an asymmetric carbon atom isalso involved in the tautomerism described above, and it is to beunderstood that the present invention encompasses any chiral form(including both pure enantiomers and racemic mixtures), as well as anytautomeric form, which has vascular damaging activity, and is not to belimited merely to any one tautomeric form or chiral form utilised withinthe formulae drawings. It is to be understood that the inventionencompasses all optical and diastereomers which have vascular damagingactivity.

It is also to be understood that certain compounds of the formula I andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which have vascular damagingactivity.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts of the invention may, for example, include acidaddition salts of the compounds of formula I as hereinbefore definedwhich are sufficiently basic to form such salts. Such acid additionsalts include for example salts with inorganic or organic acidsaffording pharmaceutically acceptable anions such as with hydrogenhalides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid.Suitable salts include hydrochlorides, hydrobromides, phosphates,sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates,acetates, benzoates, citrates, maleates, fumarates, succinates, lactatesand tartrates. In addition where the compounds of formula I aresufficiently acidic, pharmaceutically acceptable salts may be formedwith an inorganic or organic base which affords a pharmaceuticallyacceptable cation. Such salts with inorganic or organic bases includefor example an alkali metal salt, such as a sodium or potassium salt, analkaline earth metal salt such as a calcium or magnesium salt, anammonium salt or for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Compounds of Formula I may be prepared by any process known to a personskilled in the art. Such processes include, for example, solid phasesynthesis. Compounds of Formula I may be prepared by a number ofprocesses as generally described hereinbelow and more specifically inthe Examples hereinafter. In the general preparations describedhereinafter it may be necessary to employ protecting groups which arethen removed during the final stages of the synthesis. The appropriateuse of such protecting groups and processes for their removal will bereadily apparent to those skilled in the art. Processes for thepreparation of novel compounds of formula I, are provided as a furtherfeature of the invention and are as described hereinafter. Necessarystarting materials may be obtained by standard procedures of organicchemistry. The preparation of such starting materials is describedwithin the accompanying non-limiting Examples. Alternatively necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.

Thus, the following processes (a) to (i) and (i) to (iii) constitutefurther features of the present invention.

Synthesis of Compounds of Formula I

(a) Thus according to a further aspect of the invention a compound offormula I, in which R⁵ or R⁶ is a group Y⁴R³⁵ (wherein R³⁵ is as definedhereinbefore and Y⁴ is a group —OC(O)— or —NHC(O)—), can be preparedfrom a compound of formula III or IV:

(wherein X, R¹, R², R³, R⁴, R⁵, R⁶ are as defined hereinbefore and Y⁷ is—O— or —NH—), as appropriate, by standard acylation or couplingconditions including, for example, treatment of a compound of formulaIII or IV with a substituted carboxylic acid in the presence of acoupling agent such as dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and, optionally, a basesuch as an organic base for example triethylamine in a solvent such asan aprotic solvent for example dimethylformamide or in a chlorinatedsolvent for example trichloromethane or dichloromethane at a temperaturein the range from about −30° C. to about 60° C., conveniently at or nearambient temperature.

(b) In another general example a compound of formula I, in which R⁵ orR⁶ is a group Y⁴R³⁵ (wherein R³⁵ is C₁₋₇alkoxy which may be substitutedas defined hereinbefore and Y⁴ is a group —OC(O)— or —NHC(O)—), can beprepared from a compound of formula III and IV, as appropriate, bystandard acylation reactions including, for example, treatment of acompound of formula III or IV with a substituted alkylchloroformate inthe presence of a base such as an organic base for example,triethylamine or N-methylmorpholine in a solvent such as an ethersolvent for example tetrahydrofuran or in a chlorinated solvent forexample dichloromethane at a temperature in the range from about −20° C.to the reflux temperature of the solvent.

(c) In a further general example a compound of formula I, in which R⁵ orR⁶ is a group Y⁴R³⁵ (wherein R³⁵ is aminoC₁₋₇alkylamino,C₁₋₇alkylaminoC₁₋₇alkylamino, di(C₁₋₇alkyl)aminoC₁₋₇alkylamino and maybe substituted as defined hereinbefore, or is R⁵³ (wherein R⁵³ is asdefined hereinbefore) and Y⁴ is a group —OC(O)— or —NHC(O)—), can beprepared from a compound of formula III or IV, as appropriate, bystandard acylation reactions including, for example, treatment of acompound of formula III or IV with a substituted alkylisocyanate or acarbamoyl chloride in the presence of a base such as an organic base forexample triethylamine, pyridine or N-methylmorpholine in a solvent suchas an ether solvent for example tetrahydrofuran or in a chlorinatedsolvent for example dichloromethane at a temperature in the range fromabout −20° C. to the reflux temperature of the solvent.

(d) In a further example a compound of formula I, in which R⁵ or R⁶ is agroup Y⁴R³⁵ (wherein R³⁵ is a sugar moiety and Y⁴ is a group —O— or—NH—), can be prepared from a compound of formula III or IV, asappropriate, by standard glycosylation reactions including for exampletreatment of a compound of formula III or IV with a suitably protected1-bromo sugar in a solvent such as a chlorinated solvent for exampletrichloromethane or an aromatic solvent for example toluene at atemperature in the range from about 0° C. to the reflux temperature ofthe solvent, followed by deprotection. Suitable protecting groupsinclude acetyl groups for the sugar hydroxyl groups and esters for sugarcarboxylic acids.

(e) In a further example a compound of formula I in which R⁵ or R⁶ is agroup Y⁴R³⁵ (wherein R³⁵ is sulphate and Y⁴ is a group —O— or —NH—), canbe prepared from a compound of formula III or IV, as appropriate, bystandard sulphonylation reactions including for example treatment of acompound of formula III or IV with chlorosulphonic acid in the presenceof a base such as dimethylaniline in a chlorinated solvent such astrichloromethane at a temperature in the range from about −20° C. toabout 60° C., or more preferably with chlorosulphonic acid in pyridineat a temperature in the range from about −20° C. to about 60° C.

(f) In a further example a compound of formula I in which R⁵ or R⁶ is agroup Y⁴R³⁵ (wherein R³⁵ is C₁₋₇alkylphosphate and may be substituted asdefined hereinbefore and Y⁴ is a group —O— or —NH—), can be preparedfrom a compound of formula III or IV, as appropriate, by standardphosphorylation reactions including for example treatment of a compoundof formula III or IV with phosphorous oxychloride in the presence of abase such as triethylamine in a chlorinated solvent such astrichloromethane at a temperature in the range from about −20° C. toabout 60° C., followed by treatment with an alcohol, or more preferablywith alkyl dichlorophosphate in the presence of a base such aslithiumHMDS in THF at a temperature in the range from about −20° C. toabout 60° C., followed by treatment with water.

(g) Compounds of formula I in which R⁵ is amino can be prepared fromcarboxylic acids of formula V:

(wherein X, R¹, R², R³, R⁴ and R⁶ are as defined hereinbefore) viaCurtius rearrangement and hydrolysis (V. Fernholz Justus Liebigs Ann.,1950, 568, 63–72).

(h) Compounds of formula I may also be prepared from other compounds offormula I by chemical modification. Examples of such chemicalmodifications that may be applied are standard alkylation, arylation,heteroarylation, acylation, thioacylation, sulphonylation, sulphation,phosphorylation, aromatic halogenation and coupling reactions. Thesereactions may be used to add new substituents or to modify existingsubstituents. Alternatively, existing substituents in compounds offormula I may be modified by, for example, oxidation, reduction,elimination, hydrolysis or other cleavage reaction to yield othercompounds of formula I.

(i) A compound of formula I in which R⁵ or R⁶ is chloro may be preparedfrom a compound of formula III or IV by standard processes such as theSandmeyer reaction.

Thus for example a compound of formula I containing an amino group maybe acylated on the amino group by treatment with, for example, an acylhalide or anhydride in the presence of a base, for example a tertiaryamine base such as triethylamine, in for example, a solvent such as ahydrocarbon solvent e.g. dichloromethane at a temperature in the rangefor example −30° C. to 120° C., conveniently at or near ambienttemperature.

In another general example of an interconversion process an amino groupin a compound of formula I may be sulphonylated by treatment with, forexample, an alkyl or aryl sulphonyl chloride or an alkyl or arylsulphonic anhydride in the presence of a base, for example a tertiaryamine base such as triethylamine, in for example a solvent such as ahydrocarbon solvent e.g. dichloromethane at a temperature in the rangefor example −30° C. to 120° C., conveniently at or near ambienttemperature.

In a further general example a compound of formula I containing ahydroxy group can be converted into the correspondingdihydrogenphosphate ester by treatment with for example di-tert-butyldiisopropylphosphoramidite or di-tert-butyl diethylphosphoramidite inthe presence of a suitable catalyst for example tetrazole in a solventsuch as an ether solvent for example tetrahydrofuran at a temperature inthe range −40° C. to 40° C., conveniently at or near ambienttemperature, followed by treatment with an oxidising agent for example3-chloroperoxy benzoic acid at a temperature in the range −78° C. to 40°C. preferably −40° C. to 10° C. The resulting intermediate phosphatetriester is treated with an acid for example trifluoroacetic acid in asolvent such as a chlorinated solvent e.g. dichloromethane at atemperature in the range −30° C. to 40° C. conveniently at or near 0° C.to give the compound of formula I containing a dihydrogenphosphateester.

In a further general example a compound of formula I containing an amidecan be hydrolysed by treatment with for example an acid such ashydrochloric acid in a solvent such as an alcohol, for example methanolat an elevated temperature conveniently at the reflux temperature.

In another general example an O-alkyl group may be cleaved to thecorresponding alcohol (OH) by reaction with boron tribromide in asolvent such as a chlorinated solvent e.g. dichloromethane as a lowtemperature e.g. around −78° C.

In a further general example compounds of formula I may be alkylated byreaction with a suitable alkylating agent such as an alkyl halide, analkyl toluenesulphonate, an alkyl methanesulphonate or an alkyltriflate. The alkylation reaction can be carried out in the presence ofa base for example an inorganic base such as a carbonate e.g. caesium orpotassium carbonate, a hydride such as sodium hydride or an alkoxidesuch as potassium t-butoxide in a suitable solvent such as an aproticsolvent e.g. dimethylformamide or an ether solvent such astetrahydrofuran at a temperature of around −10° C. to 80° C.

Synthesis of Intermediates

(i) Compounds of formula III or IV, used as starting materials for thepreparation of compounds of the invention are either known or can beprepared from known compounds by the application of standard proceduresof organic synthesis known in the art. For example a compound of formulaVI:

(wherein X, R¹, R², R³, R⁴ and R⁵ are as defined hereinbefore), can beconverted into a compound of formula IV where Y⁷ is NH by the sequentialapplication of standard nitration conditions followed by reduction ofthe incorporated nitro group under standard reduction conditions.Suitable nitration conditions include, for example, treatment withconcentrated nitric acid in a solvent such as glacial acetic acid at atemperature from about −40° C. to about 40° C. Suitable reductionconditions include, for example, treatment with tin(II) chloride in asolvent such as hydrochloric acid, with or without an alcoholiccosolvent, at a temperature between ambient temperature and about 100°C.

(ii) Compounds of formulae III or IV can also be prepared from othercompounds of formulae III or IV by chemical modification. For example acompound of formula IV in which Y⁷ is NH can be converted into thecorresponding compound in which Y⁷ is O by treatment with sodium nitritein sulphuric acid at around 0° C. followed by heating to around 100° C.

Preparation of a compound of formula I as a single enantiomer or, whereappropriate, diastereomer may be effected by synthesis from anenantiomerically pure starting material or intermediate or by resolutionof the final product in a conventional manner.

Acid addition salts of the compounds of formula I are prepared in aconventional manner by treating a solution or suspension of the freebase I with about one equivalent of a pharmaceutically acceptable acid.Salts of compounds of formula I derived from inorganic or organic basesare prepared in a conventional manner by treating a solution orsuspension of the free acid I with about one equivalent of apharmaceutically acceptable organic or inorganic base. Alternativelyboth acid addition salts and salts derived from bases may be prepared bytreatment of the parent compound with the appropriate ion-exchange resinin a standard fashion. Conventional concentration and recrystallisationtechniques are employed in isolating the salts.

(iii) Compounds of formula V may be prepared from the correspondingcolchicine derivatives by treatment with sodium methoxide in methanolfollowed by ester hydrolysis with aqueous acid or aqueous base (V.Fernholz Justus Liebigs Ann., 1950, 568, 63–72). Compounds of formula VImay be prepared by any of the methods described for compounds of formulaI.

Many of the intermediates defined herein, for example, those of theformula III, IV, V, and VI are novel and these are provided as a furtherfeature of the invention. The preparation of these compounds is asdescribed herein and/or is by methods well known to persons skilled inthe art of organic chemistry.

Compounds according to the invention are able to destroy vasculaturethat has been newly formed such as tumour vasculature while leavingunaffected normal, mature vasculature. The identification of compoundswhich selectively, and preferably potently, damage newly-formedvasculature is desirable and is the subject of the present invention.The ability of the compounds to act in this way may be assessed, forexample, using one or more of the procedures set out below:

(a) Activity Against Tumour Vasculature Measured by Radioactive Tracer

This assay demonstrates the ability of compounds to damage selectivelytumour vasculature.

Subcutaneous CaNT tumours were initiated by injecting 0.05 ml of a crudetumour cell suspension, approximately 10⁶ cells, under the skinoverlying the rear dorsum of 12–16 week-old mice. The animals wereselected for treatment after approximately 3–4 weeks, when their tumoursreached a geometric mean diameter of 5.5–6.5 mm. Compounds weredissolved in sterile saline and injected intraperitoneally in a volumeof 0.1 ml per 10 g body weight. Tumour perfusion was measured 6 hoursafter intraperitoneal administration in tumour, kidney, liver, skin,muscle, gut and brain by the ⁸⁶RbCl extraction technique (Sapirstein,Amer. Jnl. Physiol., 1958, 193, 161–168). Tissue radioactivity measured1 minute after an intravenous injection of ⁸⁶RbCl was used to calculaterelative blood flow as a proportion of cardiac output (Hill andDenekamp, Brit. Jnl. Radiol., 1982, 55, 905–913). Five animals were usedin control and treated groups. Results were expressed as a percentage ofthe blood flow in the corresponding tissues in vehicle treated animals.

(b) Activity Against Tumour Vasculature Measured by Fluorescent Dye

This assay demonstrates the ability of compounds to damage tumourvasculature.

Tumour functional vascular volume of CaNT tumour-bearing mice wasmeasured using the fluorescent dye Hoechst 33342 according to the methodof Smith et al (Brit. Jnl. Cancer 1988, 57, 247–253). Five animals wereused in control and treated group. The fluorescent dye was dissolved insaline at 6.25 mg/ml and injected intravenously at 10 mg/kg 24 hoursafter intraperitoneal drug treatment. One minute later, animals werekilled and tumours excised and frozen; 10 μm sections were cut at 3different levels and observed under UV illumination using an Olympusmicroscope equipped with epifluorescence. Blood vessels were identifiedby their fluorescent outlines and vascular volume was quantified using apoint scoring system based on that described by Chalkley, (Jnl. Natl.Cancer Inst., 1943, 4, 47–53). All estimates were based on counting aminimum of 100 fields from sections cut at the 3 different levels.

The ability of the compounds to bind to preparations of mammaliantubulin can be evaluated by a number of methods available in theliterature, for example by following temperature initiated tubulinpolymerisation by turbidity in the absence and presence of the compound(for example O. Boye et al Med. Chem. Res., 1991, 1, 142–150).

The activity ofN-[3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,(V. Fernholz Justus Liebigs Ann., 1950, 568, 63–72), against tumourvasculature was measured by the fluorescent dye method described above.This compound decreased perfused vascular volume by 88% relative tocontrol when dosed at 50 mg/kg intraperitoneally. The IC₅₀ of thiscompound in a tubulin polymerisation assay was 58 micromolar (O. Boye etal Med. Chem. Res., 1991, 1, 142–150).

The activity of compounds Examples 2 and 3 (described hereinafter)against tumour vasculature was measured by the fluorescent dye methoddescribed hereinbefore.

Compound of Example % Decrease in vascular volume 2 95 3 45(c) HUVEC Detachment Assay

This assay examined the effects of compounds on the adherence of HUVECsto tissue culture plasticware.

HUVECs were plated in 0.2% gelatin-coated 12 well tissue culture platesat a concentration of 3×10⁴ cells per well in 1 ml TCS medium. After 24hours, when the cells were at ˜30% confluency, the cells were dosed withcompound for 40 minutes at 37° C., 5% CO₂. After this incubation themedium containing drug was pipetted off, and the cells were then gentlywashed in 2 mls of HBSS (Hanks' Balanced Salt Solution purchased fromLife Technologies Ltd, Paisley UK; Catalogue # 24020-083) to remove anydetached cells. The washing solution was then removed, and the adherentcells remaining were trypsinised using 300 μl of 1×Trypsin-EDTA solution(Life Technologies Ltd, Paisley, UK; Catalogue # 43500-019) at ambienttemperature for 2 minutes. The trypsinised cells were then made up to 1ml with TCS Biologicals medium, then centrifuged at 2000 rpm for 2minutes. The cell pellet was then resuspended in a volume of 50 μl ofTCS Biologicals medium. Total cell counts were obtained by counting thecells on a haemocytometer. The amount of cell detachment was calculatedby comparing the number of cells remaining attached following treatmentwith the number in undosed control wells.

(d) Hras5 Necrosis Model

NIH 3T3 fibroblasts transfected with Harvey ras, clone 5, (Hras5 cells)were kept in continual passage in Dulbecco's modified Eagles medium(DMEM) containing 10% foetal bovine serum (FBS) and 1% glutamine, at 37°C. in a humidified incubator gassed with 7.5% carbon dioxide and 92.5%oxygen. Cells were implanted subcutaneously into the left flank of malenude mice (8–10 weeks of age) at an inoculum of 2×10⁵ cells/mouse.Tumours were measured using calipers and randomised into groups of 2–4mice between days 9–14 after implant. Mice were dosed with compounds,either intravenously or intraperitoneally, once on day of randomisationand culled 24 hours after dosing. Compounds were dissolved in 20%hydroxypropyl beta cyclodextrin in physiological saline at pH 7 anddosed in a volume of 0.1 ml per 10 g body weight. Tumours were excised,weighed and placed in buffered formalin. Area of necrosis in individualtumours was assessed from a haematoxylin/eosin stained-slide by apathologist and scored from 0, meaning no significant change, to 10,meaning 91–100% necrosis.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula Ias defined hereinbefore or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for nasal administration oradministration by inhalation, for example as a powder or solution, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) for example as a sterilesolution, suspension or emulsion, for topical administration for exampleas an ointment or cream or for rectal administration for example as asuppository. In general the above compositions may be prepared in aconventional manner using conventional excipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5–5000 mg per squaremeter body area of the animal, i.e. approximately 0.1–100 mg/kg. A unitdose in the range, for example, 1–100 mg/kg, preferably 1–50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1–250 mg of active ingredient.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1–50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly, the optimum dosage may be determined by the practitionerwho is treating any particular patient.

According to a further aspect of the present invention there is provideda compound of the formula I or a pharmaceutically acceptable saltthereof as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

A further feature of the present invention is a compound of formula I,or a pharmaceutically acceptable salt thereof, for use as a medicament,conveniently a compound of formula I, or a pharmaceutically acceptablesalt thereof, for use as a medicament for producing a vascular damagingeffect in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of the formula I, or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for use in theproduction of a vascular damaging effect in a warm-blooded animal suchas a human being.

According to a further feature of the invention there is provided amethod for producing a vascular damaging effect in a warm-bloodedanimal, such as a human being, in need of such treatment which compriseadministering to said animal an effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof as definedhereinbefore.

The antiangiogenic treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to the antiangiogenic treatment defined hereinbefore may be:surgery, radiotherapy or chemotherapy. Such chemotherapy may include thefollowing categories of therapeutic agent:

(i) other antiangiogenic agents that work by different mechanisms fromthose defined hereinbefore (for example linomide, inhibitors of integrinαvβ3 function, angiostatin, endostatin, razoxin, thalidomide) andincluding vascular endothelial growth factor (VEGF) receptor tyrosinekinase inhibitors (RTKIs) (for example those described in InternationalPatent Applications Publication Nos. WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354 the entire disclosure of which documents isincorporated herein by reference);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrazole, vorazole, exemestane), antiprogestogens,antiandrogens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), LHRH agonists and antagonists (for examplegoserelin acetate, luprolide), inhibitors of testosterone5α-dihydroreductase (for example finasteride), anti-invasion agents (forexample metalloproteinase inhibitors like marimastat and inhibitors ofurokinase plasminogen activator receptor function) and inhibitors ofgrowth factor function, (such growth factors include for exampleepidermal growth factor (EGF), platelet derived growth factor andhepatocyte growth factor such inhibitors include growth factorantibodies, growth factor receptor antibodies, tyrosine kinaseinhibitors and serine/threonine kinase inhibitors);

(iii) biological response modifiers (for example interferon);

(iv) antibodies (for example edrecolomab); and

(v) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); antitumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);antimitotic agents (for example vinca alkaloids like vincristine andtaxoids like taxol, taxotere); enzymes (for example asparaginase);thymidylate synthase inhibitors (for example raltitrexed); topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, irinotecan).

As stated above the compounds defined in the present invention are ofinterest for their vascular damaging effects. Such compounds of theinvention are expected to be useful in the prophylaxis and treatment ofa wide range of disease states where inappropriate angiogenesis occursincluding cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,arterial restenosis, autoimmune diseases, acute inflammation,endometriosis, dysfunctional uterine bleeding and ocular diseases withretinal vessel proliferation. In particular such compounds of theinvention are expected to slow advantageously the growth of primary andrecurrent solid tumours of, for example, the colon, breast, prostate,lungs and skin.

In addition to their use in therapeutic medicine, the compounds offormula I and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of vasculardamaging agents in laboratory animals such as cats, dogs, rabbits,monkeys, rats and mice, as part of the search for new therapeuticagents.

It is to be understood that where the term “ether” is used anywhere inthis specification it refers to diethyl ether.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18–25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

Abbreviations 1,3-Dicyclohexylcarbodiimide DCCI 4-DimethylaminopyridineDMAP Tetrahydrofuran THF Diethyl azodicarboxylate DEADN,N-Dimethylformamide DMF 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimideEDCI hydrochloride Dimethyl sulphoxide DMSO Trifluoroacetic acid TFA1,1,1,3,3.3-hexamethyldisilazane HMDS

EXAMPLE 1N-[3-((N-benzyloxycarbonylalanyl)amino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide

A solution of N-benzyloxycarbonyl-(L)-alanine (63 mg, 0.28 mmol) indichloromethane (4 ml) at −20° C. was treated withN-[3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(100 mg, 0.28 mmol), (V. Fernholz Justus Liebigs Ann., 1950, 568,63–72), and 1,3-dicylcohexylcarbodiimide (134 mg, 0.31 mmol) and thesolution stirred for 16 hours at ambient temperature. Solvent wasevaporated under reduced pressure and the residue chromatographed onsilica gel, eluting with ethyl acetate to give a white solid which wastriturated with diethyl ether. The title compound (85 mg) was obtainedas a white solid.

m.p. 140–141° C.

m/e 561

EXAMPLE 2N-[3-(alanylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide

A solution ofN-[3-((N-benzyloxycarbonylalanyl)amino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(70 mg, 0.125 mmol), (prepared as described in Example 1), in ethanol (2ml) was hydrogenated at atmospheric pressure over 5% palladium on carbon(10 mg) for 2 hours. Ethanol (3 ml) was added and the solution wasfiltered through diatomaceous earth and the filtrate concentrated underreduced pressure. Trituration with ethyl acetate/diethyl ether gave thetitle compound (35 mg) as a white solid.

m.p. 170–173° C.

m/e 427

EXAMPLE 3N-[3-(4-(1-piperidinyl)piperidinylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide

A solution of N-acetyl-colchinol (300 mg, 0.84 mmol), (J. Cech F.Santacy Collect. Czech Comm 1949, 4, 532–539), in pyridine (5 ml) wastreated with 4-piperidinopiperidine carbamoyl chloride (346 mg, 1.5mmol), (K. H. Henegar et al. J. Org. Chem., 1997, 62, 6588–6597) and thesolution heated at reflux for 1 hour. The cooled mixture was filteredand the filtrate concentrated under reduced pressure. The residue waspurified on silica gel eluting with methanol to give the title compound(180 mg) as a white solid.

m.p. 168–175° C.

m/e 551

EXAMPLE 4

A solution of(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-{[(2R)-2,6-di(tertbutoxycarbonylamino)hexanoyl]amino}propanoate (1)(0.123 g; 0.162 mmol) in dichloromethane (10 ml) was treated with a 4.8Msolution of hydrogen chloride in ether (170 μl; 0.81 mmol). The mixturewas stirred at ambient temperature for 1 hour and the resultingprecipitate was filtered, washed with ether and dried to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-{[(2R)-2,6-diaminohexanoyl]amino}propanoate as a white solid.

Yield: 84%

¹H NMR spectrum (DMSOd₆): 1.39 (m, 2H); 1.58 (m, 2H); 1.74 (m, 2H); 1.89(s, 3H); 1.89 (m, 1H); 2.02 (m, 1H); 2.15 (m, 1H); 2.5 (m, 1H, signalobscured partially by DMSO peak); 2.74 (m, 2H); 2.84 (t, 2H); 3.52 (m,5H); 3.78 (s, 3H); 3.78 (m, 1H); 3.84 (s, 3H); 4.55 (m, 1H); 6.80 (s,1H); 7.1–7.15 (m, 2H); 7.35 (dd, 1H); 8.01 (br s, 2H); 8.32 (m, 2H);8.53 (d, 1H); 8.96 (t, 1H).

MS-ESI: 557 [MH]⁺

Elemental analysis: Found C 53.8 H 6.8 N 8.7 C₂₉H₄₀N₄O₇; 0.8 H₂O, 2 HClRequires C 53.9 H 7.2 N 8.1%

The starting material was prepared as follows:

A mixture of3-{[(2R)-2,6-di(tertbutoxycarbonylamino)hexanoyl]amino}propanoic acid(2) (0.178 g; 0.5 mmol), DCCI (0.124 g; 0.6 mmol), DMAP (0.013 g; 0.1mmol) and N-acetyl-colchicinol (0.25 g; 1.2 mmol) in dichloromethane wasstirred under argon atmosphere at ambient temperature for 5 hours. Afterfiltration of the insoluble material the residue was purified by flashchromatography eluting with dichloromethane/ethanol (95/5) to give (1).

Yield: 32%

¹H NMR spectrum (DMSOd₆): 1.15–1.6 (m, 6H); 1.36 (s, 18H); 1.87 (s, 3H);1.87 (m, 1H); 2.05 (m, 1H); 2.15 (m, 1H); 2.50 (m, 1H, signal obscuredpartially by DMSO peak); 2.75 (t, 2H); 2.86 (m, 2H); 3.85 (m, 2H); 3.51(s, 3H); 3.78 (s, 3H); 3.84 (s, 3H); 3.85 (m, 1H); 4.55 (m, 1H); 3.7–3.8(m, 2H); 6.8 (s, 1H); 7.08 (s, 1H); 7.1 (m, 1H); 7.32 (dd, 1H); 8.01 (t,1H); 8.35 (d, 1H).

EXAMPLE 5

A solution of(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (4) (0.36 g; 0.61mmol) in dichloromethane (5 ml) was treated with a 4.8M solution ofhydrogen chloride in ether (1 ml). The mixture was stirred at ambienttemperature for 1 hour. After dilution with ether, the resultingprecipitate was filtered, washed with ether and dried to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-[(2-aminoacetyl)amino]propanoate.

Yield: 98%

¹H NMR spectrum (DMSOd₆): 1.90 (m, 1H); 1.90 (s, 3H); 2.05 (m, 1H); 2.3(m, 1H); 2.9 (m, 1H, signal obscured partially by DMSO peak); 2.84 (t,2H); 3.52 (s, 3H); 3.52 (m, 2H); 3.6 (m, 2H, signal obscured partiallyby H₂O peak); 3.8 (s, 3H); 3.86 (s, 3H); 4.55 (m, 1H); 6.82 (s, 1H);7.13 (m, 2H); 7.37 (dd, 1H); 8.1 (br s, 2H); 8.46 (d, 1H); 8.67 (t, 1H).

MS-ESI: 486 [MH]⁺

Elemental analysis: Found C 54.8 H 6.2 N 7.7 C₂₅H₃₁N₃O₇; 0.8 H₂O, 1.3HCl Requires C 54.8 H 6.3 N 7.6%

The starting material was prepared as follows:

A solution of β-alanine ethyl ester hydrochloride salt (5) (3.07 g; 0.02mmol), N-(tertbutoxycarbonyl)glycine (3.5 g; 0.02 mmol), DCCI (4.12 g;0.02 mmol) and 4-methylmorpholine (2.2 ml) in dichloromethane (60 ml)was stirred overnight under argon atmosphere at ambient temperature.After filtration the residue was purified by flash chromatographyeluting with dichloromethane/ethanol (96/4) to give ethyl3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (6).

Yield: 62%

¹H NMR spectrum (CDCl₃): 1.27 (t, 3H); 1.45 (s, 9H); 3.55 (m, 2H); 3.77(d, 2H); 4.15 (q, 2H); 5.3 (br s, 2H); 6.56 (br s, 2H).

A solution of (6) at 0° C. (3.43 g; 0.012 mmol) in methanol (40 ml) wastreated with 2N sodium hydroxide (6.9 ml; 0.013 mmol). The mixture wasstirred at ambient temperature for 90 minutes. After evaporation of themethanol and removal of the insoluble material by filtration, thesolution was adjusted to pH5 with 6N hydrochloric acid. The mixture wasextracted with dichloromethane and the organic layer evaporated todryness to give 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoic acid(7).

Yield: 16%

¹H NMR spectrum (CDCl₃+CD₃CO₂D): 1.44 (s, 9H); 2.61 (t, 2H); 3.5 (m,2H); 3.80 (m, 2H).

A mixture of N-acetyl-colchicinol (0.357 g; 1 mmol), DCCI (0.248 g; 1.2mmol), DMAP (0.025 g; 0.2 mmol) and (7) (0.246 g; 1 mmol) indichloromethane (7 ml) was stirred under argon atmosphere for 5 hours.After removal of the insoluble material by filtration the residue waspurified by flash chromatography eluting with dichloromethane/ethanol(92/8) to give (4) as a foam.

Yield: 61%

¹H NMR spectrum (DMSOd₆): 1.4 (s, 9H); 1.89 (s, 3H); 1.89 (m, 1H); 2.07(m, 1H); 2.18 (m, 1H); 2.5 (m, 1H, signal obscured partially by DMSOpeak); 2.77 (t, 2H); 3.45 (m, 2H); 3.52 (s, 3H); 3.5 (m, 2H); 3.8 (s,3H); 3.85 (s, 3H); 4.55 (m, 1H); 6.81 (s, 1H); 6.97 (t, 1H); 7.11 (m,2H); 7.35 (dd, 1H); 8.01 (t, 1H); 8.38 (d, 1H).

EXAMPLE 6

Triethylamine (70 μl; 0.5 mmol) and methyl chloroformate (39 μl; 0.5mmol) were added to a solution of N-acetyl-colchicinol (0.178 g; 0.5mmol) in THF (3 ml). The mixture was stirred at ambient temperature for90 minutes. After removal of the insoluble material by filtration theresidue was purified by flash chromatography eluting withdichloromethane/ethanol (98/2) to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylmethyl carbonate.

Yield: 75%

¹H NMR spectrum (DMSOd₆): 1.87 (s, 3H); 1.87 (m, 1H); 2.05 (m, 1H); 2.17(m, 1H); 2.5 (m, 1H, signal obscured partially by DMSO peak); 3.52 (s,3H); 3.78 (s, 3H); 3.84 (s, 3H); 3.85 (s, 3H); 4.52 (m, 1H); 6.8 (s,1H); 7.16–7.18 (m, 2H); 7.36 (dd, 1H); 8.38 (d, 1H).

MS-ESI: 438 [MH]⁺

Elemental analysis: Found C 61.7 H 6.2 N 3.3 C₂₂H₂₅NO₇; 0.7 H₂O RequiresC 61.6 H 6.2 N 3.4%

EXAMPLE 7

DEAD (0.118 g; 0.75 mmol), triphenylphosphine (0.196 g; 0.75 mmol) and4-(2-hydroxyethyl)morpholine (61 μl; 0.5 mmol) were added to a solutionof N-acetyl-colchicinol (0.178 g; 0.5 mmol) in dichloromethane (5 ml)under argon atmosphere. The mixture was stirred at ambient temperaturefor 6 hours. After evaporation the residue was purified by flashchromatography eluting with a gradient of 2–10% ethanol/dichloromethaneto giveN-[(5S)-3-(2-morpholinoethoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 37%

¹H NMR spectrum (DMSOd₆): 1.85 (m, 1H); 1.87 (s, 3H); 2.05 (m, 1H); 2.15(m, 1H); 2.39 (m, 2H); 2.5 (m, 3H, signal obscured partially by DMSOpeak); 2.72 (t, 2H); 3.46 (s, 3H); 3.54–3.6 (s, 4H); 3.77 (s, 3H); 3.82(s, 3H); 4.09–4.12 (m, 2H); 4.55 (m, 1H); 6.76 (s, 1H); 6.86–6.90 (m,2H); 7.23 (dd, 2H); 8.35 (d, 1H).

MS-ESI: 471 [MH]⁺

Elemental analysis: Found C 66.4 H 7.3 N 6.0 C₂₆H₃₄N₂O₆ Requires C 66.6H 7.3 N 6.3%

EXAMPLE 8

Using an analogous procedure to that described for Example 7,N-acetyl-colchicinol was reacted with 4-(2-hydroxyethyl)piperidine togiveN-[(5S)-3-(2-piperidinoethoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 20%

¹H NMR spectrum (DMSOd₆): 1.39 (m, 2H); 1.49 (m, 4H); 1.80 (m, 1H); 1.88(s, 3H); 2.05 (m, 1H); 2.15 (m, 1H); 2.45 (m, 4H); 2.5 (m, 1H, signalobscured partially by DMSO peak); 2.67 (m, 2H); 3.46 (s, 3H); 3.77 (s,3H); 3.82 (s, 3H); 4.08 (t, 2H); 4.55 (m, 1H); 6.76 (s, 1H); 6.86–6.9(m, 2H); 7.22 (dd, 1H); 8.35 (d, 1H).

MS-ESI: 469 [MH]⁺

Elemental analysis: Found C 68.7 H 7.8 N 5.9 C₂₇H₃₆N₂O₅; 0.2 H₂ORequires C 68.5 H 8.0 N 6.1%

EXAMPLE 9

Using an analogous procedure to that described for Example 7,N-acetyl-colchicinol was reacted with4-(3-hydroxypropyl)-1-methylpiperazine to giveN-[(5S)-3-(3-(4-methylpiperazin-1-yl)propoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 22%

¹H NMR spectrum (DMSO d₆): 1.88 (s, 3H); 1.85–1.9 (m, 3H); 2.04–2.16 (m,5H); 2.32–2.53 (m, 11H, signals obscured partially by DMSO peak); 3.47(s, 3H); 3.78 (s, 3H); 3.83 (s, 3H); 4.03 (t, 2H); 4.55 (m, 1H); 6.72(s, 1H); 6.85 (dd, 1H); 6.9 (m, 1H); 7.23 (d, 1H); 8.23 (d, 1H).

MS-ESI: 498 [MH]⁺

Elemental analysis: Found C 64.8 H 8.0 N 8.1 C₂₈H₃₉N₃O₅; 0.8 H₂ORequires C 64.7 H 7.7 N 8.2%0.1 dichloromethane

EXAMPLE 10

A solution ofN-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(0.3 g; 0.779 mmol), (Med. Chem. Res. 1991, 142), DCCI (0.322 g; 1.55mmol), DMAP (0.069 g; 0.389 mmol) and 4-(3-aminopropyl)morpholine (170μl; 1.17 mmol) in dichloromethane (6 ml) was stirred under argonatmosphere overnight. After removal of the insoluble material byfiltration, the residue was purified on reverse phase silica elutingwith a gradient of 40–50% methanol/ammonium carbonate buffer (2 g/l,pH7). The appropriate fractions were evaporated to dryness andtriturated in ether to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-N-(3-morpholinopropyl)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxamideas a white solid.

Yield: 30%

¹H NMR spectrum (DMSOd₆): 1.7 (m, 2H); 1.91 (s, 3H); 1.91 (m, 1H); 2.05(m, 1H); 2.2 (m, 1H); 2.37 (m, 6H); 2.5 (m, 3H, signal obscuredpartially by DMSO peak); 3.51 (s, 3H); 3.58 (m, 4H); 3.8 (s, 3H); 3.86(s, 3H); 4.58 (m, 1H); 6.83 (s, 1H); 7.39 (dd, 1H); 7.74 (m, 1H); 7.84(s, 1H); 8.51 (m, 2H).

MS-ESI: 512 [MH]⁺

Elemental analysis: Found C 64.8 H 7.3 N 8.1 C₂₈H₃₇N₃O₆; 0.4 H₂ORequires C 64.5 H 7.3 N 8.0%

EXAMPLE 11

Using an analogous procedure to that described for Example 10,N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamidewas reacted with 1-(2-aminoethyl)piperidine to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-N-(2-piperidinoethyl)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxamide.

Yield: 43%

¹H NMR spectrum (DMSOd₆): 1.38 (m, 2H); 1.49 (m, 4H); 1.89 (s, 3H); 1.89(m, 1H); 2.05 (m, 1H); 2.18 (, 1H); 2.4–2.5 (m, 4H); 2.5 (m, 1H, signalobscured partially by DMSO peak); 3.38 (m, 4H); 3.49 (s, 3H); 3.79 (s,3H); 3.84 (s, 3H); 4.58 (m, 1H); 6.81 (s, 1H); 7.37 (d, 1H); 7.71 (m,1H); 7.81 (s, 1H); 8.35 (t, 1H); 8.49 (d, 1H).

MS-ESI: 496 [MH]⁺

Elemental analysis: Found C 66.4 H 7.6 N 8.3 C₂₈H₃₇N₃O₅; 0.6 H₂ORequires C 66.1 H 7.7 N 8.3%

EXAMPLE 12

A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), 4-nitrophenylchloroformate (0.262 g; 1.3 mmol) and triethylamine (182 μl; 1.3 mmol)in dichloromethane (10 ml) was stirred, under argon atmosphere, atambient temperature for 90 minutes. 4-(4-Aminobutyl)morpholine (0.237 g;1.5 mmol) was then added and the mixture was further stirred for 4hours. After evaporation to dryness the residue was purified by flashchromatography eluting with a gradient of 0–12% ethanol/dichloromethaneto give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylN-(4-morpholinobutyl)carbamate as a white foam.

Yield: 24%

¹H NMR spectrum (DMSOd₆): 1.49 (m, 4H); 1.86 (s, 3H); 1.86 (m, 1H); 2.05(m, 1H); 2.18 (m, 1H); 2.26–2.34 (m, 6H); 2.5 (m, 1H, signal obscuredpartially by DMSO peak); 3.08 (m, 2H); 3.51 (s, 3H); 3.57 (m, 4H); 3.78(s, 3H); 3.84 (s, 3H); 4.55 (m, 1H); 6.79 (s, 1H); 7.02 (m, 2H); 7.29(d, 1H); 7.78 (t, 1H); 8.39 (d, 1H).

MS-ESI: 542 [MH]⁺

Elemental analysis: Found C 63.5 H 7.3 N 7.7 C₂₉H₃₉N₃O₇; 0.4 H₂ORequires C 63.4 H 7.3 N 7.7%

EXAMPLE 13

A solution ofN-[(5S)-3-(2,3-epoxypropoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.092 g; 0.22 mmol) and morpholine (40 μl; 0.44 mmol) in methanolwas heated at reflux for 4 hours. After evaporation to dryness theresidue was purified by flash chromatography eluting withdichloromethane/ethanol (90/10) to giveN-[(5S)-3-(2-hydroxy-3-morpholinopropoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a yellow foam.

Yield: 55%

¹H NMR spectrum (DMSOd₆): 1.88 (s, 3H); 1.88 (m, 1H); 2.05 (m, 1H); 2.15(m, 1H); 2.42–2.5 (m, 4H); 2.5 (m, 1H, signal obscured partially by DMSOpeak); 3.33–3.4 (m, 4H); 3.46 (s, 3H); 3.57 (m, 2H); 3.77 (s, 3H); 3.82(s, 3H); 3.90 (m, 1H); 3.99 (m, 2H); 4.52 (m, 1H); 4.9 (t, 1H); 6.76 (s,1H); 6.86–6.9 (m, 2H); 7.23 (d, 1H); 8.37 (d, 1H).

MS-ESI: 501 [MH]⁺

Elemental analysis: Found C 64.8 H 7.3 N 5.6 C₂₇H₃₆N₂O₇ Requires C 64.5H 7.5 N 5.5%

The starting material was prepared as follows:

A solution of N-acetyl-colchicinol (0.179 g; 0.5 mmol), potassiumcarbonate (0.083 g; 0.6 mmol) and epichlorohydrin (0.059 g; 0.75 mmol)in DMF (2 ml) was heated at 80° C. for 5 hours. The mixture was pouredinto saturated sodium hydrogen carbonate and extracted with ethylacetate. The organic phase was washed with brine, dried (MgSO₄) andevaporated to give an oil which was purified by flash chromatographyeluting with a 2–4% gradient of ethanol/dichloromethane to give (1).

Yield: 46%

¹H NMR spectrum (DMSOd₆): 1.88 (s, 3H); 1.84 'm, 1H); 2.05 (m, 1H); 2.15(m, 1H); 2.5 (m, 1H partially obscured by DMSO peak); 2.75 (m, 1H); 2.88(m, 1H); 3.42 (m, 1H); 3.46 (s, 3H); 3.77 (s, 3H); 3.82 (s, 3H); 3.87(m, 1H); 4.35 (m, 1H); 4.52 (m, 1H); 6.76 (s, 1H); 6.88–6.94 (m, 2H);7.24 (d, 1H); 8.35 (d, 1H).

EXAMPLE 14

A solution of methyl(5S)-9,10,11-trimethoxy-5-amino-3-hydroxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-2-carboxylate(1) (0.373 g; 1 mmol) methyl chloroformate (0.17 ml; 2.2 mmol) andtriethylamine was stirred at ambient temperature overnight. Afterevaporation to dryness, the residue was purified by flashchromatography, eluting with ethanol/dichloromethane (2/98) and furtherpurified by preparative HPLC on reverse phase silica eluting withmethanol/ammonium carbonate buffer (2 g/l pH7) (50/50) to give methyl(5S)-9,10,11-trimethoxy-5-[(methoxycarbonyl)amino]-3-[(methoxycarbonyl)oxy]-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-2-carboxylate.

Yield: 48%

¹H NMR spectrum (DMSOd₆): 1.84–2.09 (m, 2H); 2.19–2.31 (m, 1H); 2.57 (m,1H, partially obscured by DMSO peak); 3.50 (s, 3H); 3.55 (s, 3H); 3.81(s, 3H); 3.82 (s, 3H); 3.86 (s, 3H); 3.87 (s, 3H); 4.28–4.389 (m, 1H);6.85 (s, 1H); 7.24 (s, 1H); 7.88–7.97 (m, 1H); 7.91 (s, 1H).

MS-ESI: 512 [MNa]⁺

Elemental analysis: Found C 58.7 H 5.7 N 3.0 C₂₄H₂₇NO₁₀ Requires C 58.9H 5.6 N 2.9%

The starting material was prepared as follows:

A solution of methyl(5S)-9,10,11-trimethoxy-5-acetylamino-3-hydroxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-2-carboxylate(2) (Collect. Czech. Chem. Communi. 64, 217 (1999)) in a mixture of 6Nhydrochloric acid and methanol (30/70) was heated at reflux for 8 hours.The mixture was adjusted to pH8 by addition of sodium carbonate.Extraction with dichloromethane and purification by flash chromatography(elution with dichloromethane/methanol (94/6)) gave (1) as a foam.

¹H NMR spectrum (DMSOd₆): 1.61 (m, 1H); 2.04 (m, 1H); 2.28 (m, 1H); 2.45(m, 1H); 3.50 (s, 3H); 3.54 (m, 1H); 3.77 (s, 3H); 3.83 (s, 3H); 3.90(s, 3H); 6.77 (s, 1H); 7.30 (s, 1H); 7.73 (s, 1H); 1.57 (br s, 1H).

EXAMPLE 15

A solution of(5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol(1) (0.9; 0.71 mmol), methyl chloroformate (0.061 ml; 0.782 mmol) andtriethylamine (0.109 ml; 0.782 mmol) in acetonitrile (8 ml) was stirredunder argon atmosphere at 40° C. for 4 hours. After evaporation todryness, the residue was purified by flash chromatography eluting withethanol/dichloromethane (2/98) to give(5S)-5-{[(dimethylamino)sulphonyl]amino}-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylmethyl carbonate.

Yield: 32%

¹H NMR spectrum (DMSOd₆): 1.93–2.03 (m, 2H); 2.12–2.17 (m, 1H); 2.46 (s,6H); 2.45–2.55 (m, 1H); 3.46 (s, 3H); 3.79 (s, 3H); 3.85 (s, 3H); 3.87(s, 3H); 3.94–4.10 (m, 1H); 6.82 (s, 1H); 7.21 (d, 1H); 7.37 (d, 1H);7.43 (s, 1H); 7.93 (br s, 1H).

MS-ESI: 503 [MNa]⁺

Elemental analysis Found C 55.2 H 6.1 N 5.8 S 6.3 C₂₂H₂₈N₂O₈S Requires C55.0 H 5.9 N 5.8 S 6.7%

EXAMPLE 16

A solution ofN-[(5S)-3-(4-chloromethylphenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.308 g; 0.604 mmol), 1-methylpiperazine (0.088 ml; 0.785 mmol) andsodium iodide (0.02 g; 0.121 mmol) in acetonitrile (10 ml) was stirredunder argon atmosphere overnight. After evaporation to dryness, theresidue was purified by flash chromatography eluting with a 5–12%gradient of methanol/dichloromethane. After evaporation of theappropriate fractions, the solid was triturated in ether/pentane to giveN-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a solid.

Yield: 75%

¹H NMR spectrum (DMSOd₆): 1.86 (s, 3H); 1.83–1.98 (m, 1H); 2.00–2.26 (m,2H); 2.31 (br s, 3H); 2.4–2.6 (m, 8H); 2.53–2.59 (m, 1H); 3.54 (s, 3H);3.62 (s, 2H); 3.80 (s, 3H); 3.85 (s, 3H); 4.53–4.64 (m, 1H); 6.82 (s,1H); 7.20–7.25 (m, 2H); 7.41 (d, 1H); 7.56 (d, 2H); 8.13 (d, 2H); 8.39(d, 1H).

MS-ESI: 574 [MH]⁺

The starting material was prepared as follows

A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), EDCI (0.23 g; 1.2mmol), DMAP (0.025 g; 0.2 mmol) and 4-chloromethylbenzoic acid (0.205 g;1.2 mmol) in dichloromethane (8 ml) was stirred under argon atmosphereovernight. After evaporation to dryness, the residue was purified byflash chromatography eluting with dichloromethane/ethanol (98/2) to give(1).

Yield: 72%

¹H NMR spectrum (DMSOd₆): 1.86 (s, 3H); 1.91 (m, 1H); 1.04–2.14 (m, 1H);2.14–2.67 (m, 1H); 2.57 (m, 1H; partially obscured by DMSO peak); 3.54(s, 3H); 3.80 (s, 3H); 3.86 (s, 3H); 4.54–4.64 (m, 1H); 4.91 (s, 2H);6.83 (s, 1H); 7.21–7.28 (m, 2H); 7.42 (d, 1H); 7.70 (d, 2H); 8.14 (d,2H); 8.40 (d, 1H).

EXAMPLE 17

Using an analogous procedure to that described for Example 16,N-[(5S)-3-(4-chloromethylphenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamidewas reacted with morpholine to giveN-[(5S)-3-(4-{morpholinomethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 86%

¹H NMR spectrum (DMSOd₆): 1.90 (s, 3H); 1.88–2.01 (m, 1H); 2.06–2.30 (m,2H); 2.43 (br s, 4H); 2.54–2.63 (m, 1H); 3.30 (m, 2H); 3.58 (s, 3H);3.62–3.67 (m, 6H); 3.84 (s, 3H); 3.89 (s, 3H); 4.57–4.67 (m, 1H); 3.86(s, 1H); 7.23–7.30 (m, 2H); 7.45 (d, 1H); 7.61 (d, 1H); 8.17 (d, 1H);8.43 (d, 1H).

MS-ESI: 561 [MH]⁺

Elemental analysis Found C 66.1 H 6.5 N 4.9 C₃₂H₃₆N₂O₇ ; 0.3dichloromethane Requires C 66.2 H 6.3 N 4.8%

EXAMPLE 18

A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), EDCI (0.23 g; 1.2mmol), DMAP (0.025 g; 0.2 mmol) and 3-(4-carboxyphenyl)propionic acid(0.233 g; 1.2 mmol) was stirred at ambient temperature overnight. Afterremoval of the solvent by evaporation, the residue was purified bypreparative HPLC on reverse phase silica eluting with methanol/ammoniumcarbonate buffer (2 g/l pH7) (50/50) to give4-(3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3-oxopropyl)benzoicacid.

Yield: 70%

¹H NMR spectrum (DMSOd₆): 1.82–1.93 (m, 4H); 1.97–2.22 (m, 2H);2.39–2.63 (m, 1H); 2.93–2.99 (m, 2H); 2.99–3.06 (m, 2H); 3.51 (s, 3H);3.78 (s, 3H); 3.84 (s, 3H); 3.47–3.56 (m, 1H); 6.89 (s, 1H); 6.94 (d,1H); 6.99 (dd, 1H); 7.30–7.37 (m, 3H); 7.85 (d, 2H); 8.46 (d, 1H).

MS-ESI: 534 [MH]⁺

EXAMPLE 19

A solution ofN-[(5S)-3-phenoxycarbonylamino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.1 g; 0.21 mmol) and 4-(3-aminopropyl)morpholine (0.095 g; 0.66mmol) in DMSO (1 ml) was stirred at ambient temperature for 1 hour. Themixture was purified by preparative HPLC on reverse phase silica elutingwith methanol/ammonium carbonate buffer (2 g/l, pH7) (40/60) to give,after evaporation,N-[(5S)-9,10,11-trimethoxy-3-([(3-morpholinopropyl)amino]carbonylamino)-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a foam.

Yield: 84%

¹H NMR spectrum (DMSOd₆): 1.6 (m, 2H); 1.88 (s, 3H); 1.90 (m, 1H);2.0–2.2 (m, 2H); 2.3–2.4 (m, 6H); 2.45 (m, 1H, signal obscured by DMSOpeak); 3.15 (m, 2H); 3.47 (s, 3H); 3.6 (m, 4H); 3.78 (s, 3H); 3.83 (d,3H); 4.47 (m, 1H); 6.13 (t, 1H); 6.76 (s, 1H); 7.16 (d, 1H); 7.29 (d,1H); 7.37 (dd, 1H); 8.37 (d, 1H); 8.47 (s, 1H).

MS-ESI: 527 [MH]⁺

Elemental analysis: Found C 63.4 H 7.4 N 10.6 C₂₈H₃₈N₄O₆; 0.1 H₂ORequires C 63.6 H 7.3 N 10.6%

The starting material was prepared as follows:

Pyridine (570 μl; 7 mmol) and phenyl chloroformate (720 μl; 10.3 mmol)were added to a solution ofN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(2) cooled at 0° C. (2 g; 5.6 mmol) in THF (40 ml), under argonatmosphere. The mixture was stirred at 0° C. for 5 minutes and then atambient temperature for 1 hour. The mixture was extracted with ethylacetate. The organic phase was washed with 1M hydrochloric acid,saturated sodium hydrogen carbonate and brine. After evaporation todryness the solid was triturated with ether and hexane to give (1) as asolid.

Yield: 89%

¹H NMR spectrum (DMSOd₆): 1.82 (s, 3H); 1.85 (m, 1H); 2.10 (m, 2H); 2.5(m, 1H, signal obscured by DMSO peak); 3.47 (s, 3H); 3.77 (s, 3H); 3.82(s, 3H); 4.48 (m, 1H); 6.77 (s, 1H); 7.20–7.50 (m, 7H); 7.55 (s, 1H);8.38 (d, 1H); 9.31 (s, 1H).

EXAMPLE 20

Using an analogous procedure to that described for Example 19,N-[(5S)-3-phenoxycarbonylamino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) was reacted with 4-(2-hydroxyethyl)morpholine and the mixture washeated at 60° C. for 2 hours to giveN-[(5S)-3-(2-morpholinoethoxycarbonylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 84%

¹H NMR spectrum (DMSOd₆): 1.89 (s, 3H); 1.90 (m, 1H); 2.0–2.2 (m, 2H);2.4–2.45 (m, 4H); 2.46 (m, 1H, signal obscured by DMSO peak); 2.6 (t,2H); 3.42 (s, 3H); 3.59 (m, 4H); 3.78 (s, 3H); 3.84 (s, 3H); 4.22 (m,2H); 4.44 (m, 1H); 6.78 (s, 1H); 7.22 (d, 1H); 7.39 (dd, 1H); 7.50 (s,1H); 8.39 (d, 1H); 9.73 (s, 1H).

MS-ESI: 514 [MH]⁺

Elemental analysis: Found C 60.4 H 6.6 N 8.0 C₂₇H₃₅N₃O₇; 1.1 H₂ORequired C 60.8 H 7.0 N 7.9%

EXAMPLE 21

A solution ofN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.2 g; 0.56 mmol), N,N-dimethylglycine (0.058 g; 0.56 mmol), EDCI(0.14 g; 0.73 mmol) and DMAP (0.014 g; 0.11 mmol) in dichloromethane (8ml) was stirred at ambient temperature overnight. The mixture was washedwith water and the organic phase was evaporated and purified bypreparative HPLC on reverse phase silica eluting with methanol/ammoniumcarbonate buffer (2 g/l, pH7) (40/60) to give, after evaporation,N-[(5S)-3-(N,N-dimethylaminoacetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a white foam.

Yield: 57%

¹H NMR spectrum (DMSOd₆): 1.90 (s, 3H); 1.93 (m, 1H); 2.0–2.2 (m, 2H);2.31 (s, 6H); 2.5 (m, 1H, signal partially obscured by DMSO peak); 3.09(d, 1H); 3.10 (d,1H); 3.48 (s, 3H); 3.79 (s, 3H); 3.84 (s, 3H); 4.5 (m,1H); 6.78 (s, 1H); 7.25 (d, 1H); 7.6 (m, 2H); 8.4 (d, 1H); 9.73 (s, 1H).

MS-ESI: 442 [MH]⁺

Elemental analysis: Found C 63.0 H 7.0 N 9.2 C₂₄H₃₁N₃O₅; 0.8 H₂ORequired C 63.2 H 7.2 N 9.2%

EXAMPLE 22

Using an analogous procedure to that described for Example 21,N-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamidewas reacted with 1-piperidinepropionic acid to giveN-[(5S)-3-(3-piperidinopropanoylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 61%

¹H NMR spectrum (DMSOd₆): 1.40 (m, 2H); 1.55 (m, 4H); 1.89 (s, 3H); 1.90(m, 1H); 2.0–2.2 (m, 2H); 2.4 (br s, 4H); 2.45 (m, 2H); 2.5 (m, 1H,signal obscured by DMSO peak); 2.62 (m, 2H); 3.47 (s, 3H); 3.79 (s, 3H);3.84 (s, 3H); 4.45 (m, 1H); 6.78 (s, 1H); 7.24 (d, 1H); 7.5 (s, 1H);7.58 (dd, 1H); 8.40 (d, 1H).

MS-ESI: 496 [MH]⁺

Elemental analysis: Found C 65.7 H 7.4 N 8.2 C₂₈H₃₇N₃O₅ Required C 65.7H 7.6 N 8.2%

EXAMPLE 23

A solution ofN-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.385 g; 1 mmol), EDCI (0.248 g; 1.3 mmol), DMAP (0.248 g; 0.2mmol) and 4-(2-hydroxyethyl)morpholine (127 μl; 1.05 mmol) was stirredat ambient temperature overnight. After evaporation to dryness theresidue was purified by preparative HPLC on reverse phase silica elutingwith a 40–60% gradient of methanol/ammonium carbonate buffer (2 g/l,pH7) to give, after evaporation,N-[(5S)-3-(2-morpholinoethoxycarbonyl)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a solid.

Yield: 47%

¹H NMR spectrum (DMSOd₆): 1.88 (s, 3H); 1.88–2.05 (m, 2H); 2.2 (m, 1H);2.5 (m, 5H, signal obscured by DMSO peak); 2.7 (m, 2H); 3.5 (s, 3H); 3.6(m, 4H); 3.79 (s, 3H); 3.85 (s, 3H); 4.4 (m, 2H); 4.55 (m, 1H); 6.82 (s,1H); 7.47 (d, 1H); 7.89 (dd, 1H); 7.95 (d, 1H); 8.58 (d, 1H).

MS-ESI: 499 [MH]⁺

Elemental analysis: Found C 63.2 H 6.7 N 5.5 C₂₇H₃₄N₂O₇; 0.6 H₂ORequired C 65.0 H 6.9 N 5.6%

EXAMPLE 24

A solution of methyllithium in ether (1.6 M; 2.14 ml; 3.4 mmol) wasadded at −78° C. under argon atmosphere to dry THF (5 ml). After 5minutes a solution ofN-[(5S)-3-(methoxycarbonyl)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.274 g; 0.68 mmol) in THF (11 ml) was added. The mixture wasstirred at −78° C. for 30 minutes, allowed to warm up and furtherstirred at ambient temperature for 90 minutes. After removal of thesolvents by evaporation, the residue was taken up in an aqueous ammoniumchloride/ethyl acetate mixture and extracted. The organic phase wasevaporated and purified by flash chromatography eluting with ethylacetate to giveN-[(5S)-3-(1-hydroxy-1-methylethyl)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a white foam.

Yield: 45%

¹H NMR spectrum (DMSOd₆): 1.45 (s, 3H); 1.48 (s, 3H); 1.86 (m, 1H); 1.88(s, 3H); 2.03 (m, 1H); 2.15 (m, 1H); 2.5 (m, 1H, signal obscured by DMSOpeak); 3.5 (s, 3H); 3.77 (s, 3H); 3.83 (s, 3H); 6.77 (s, 1H); 7.23 (d,1H); 7.35 (dd, 1H); 7.5 (d, 1H); 8.43 (d, 1H).

MS-ESI: 422.1 [MNa]⁺

Elemental analysis: Found C 66.5 H 7.3 N 3.5 C₂₃H₂₉NO₅; 0.8 H₂O RequiredC 66.7 H 7.5 N 3.4%

EXAMPLES 25 AND 26

A suspension of(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-carboxylate(2.28 ml; 5.7 mmol) and lithium aluminium hydride (0.216 g; 22.8 mmol)in a mixture of THF (10 ml) and ether (60 ml) was stirred at refluxunder argon atmosphere overnight. After addition of water (60 ml), themixture was stirred for 2 hours. The resulting solid was filtered andthe filtrate was evaporated and purified by flash chromatography elutingwith a 5–10% gradient of methanol/dichloromethane to give, afterevaporation,N-[(5S)-3-hydroxymethyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(yield: 33%) and[(5S)-5-(ethylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methanol(yield: 47%).

EXAMPLE 25

¹H NMR spectrum (DMSOd₆): 1.86 (m, 1H); 1.87 (s, 3H); 2.01 (m, 1H); 2.14(m, 1H); 2.48 (m, 1H, signal obscured by DMSO peak); 3.46 (s, 3H); 3.77(s, 3H); 3.83 (s, 3H); 4.54 (m, 3H); 5.21 (t, 1H); 6.78 (s, 1H); 7.27(m, 2H); 7.32 (s, 1H); 8.42 (d, 1H).

MS-ESI: 394.1 [MH]⁺

Elemental analysis: Found C 66.0 H 6.8 N 3.7 C₂₁H₂₅NO₅; 0.5 H₂O RequiresC 66.3 H 6.9 N 3.7%

EXAMPLE 26

¹H NMR spectrum (DMSOd₆): 1.90 (s, 3H); 1.90 (m, 1H); 2.01 (m, 1H); 2.20(m, 1H); 2.5 (m, 1H, signal obscured by DMSO peak); 3.53 (s, 3H); 3.78(s, 3H); 3.85 (s, 3H); 4.53 (m, 1H); 6.84 (s, 1H); 7.50 (d, 1H); 7.72(d, 1H); 7.77 (dd, 1H); 8.45 (d, 1H).

MS-ESI: 389 [MNa]⁺

EXAMPLE 27

A solution of(5S)-5-(ethylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylditertbutyl phosphate (1) (0.215 g; 0.391 mmol) in 1M hydrogen chloridesolution in 1,4-dioxane (2 ml) was stirred at ambient temperatureovernight. After addition of ether (20 ml) the resulting precipitate wasfiltered, washed with ether and dried to give(5S)-5-(ethylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yldihydrogen phosphate.

Yield: 88%

¹H NMR spectrum (DMSOd₆): 1.04 (t, 3H); 1.78 (m, 1H); 2.0 (m, 1H); 2.32(m, 1H); 2.5 (m, 3H, signals obscured by DMSO peak); 3.48 (s, 3H); 3.5(m, 1H,); 3.78 (s, 3H); 3.84 (s, 3H); 4.79 (m, 3H); 6.78 (s, 1H); 7.27(s, 2H); 7.66 (s, 1H).

MS-ESI: 460 [MH]⁺

The starting material was prepared as follows:

1H-Tetrazole (0.182 g; 2.6 mmol) was added, under argon atmosphere, to asolution of[(5S)-5-(ethylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methanol,(prepared as described in Example 26), (0.3 g; 0.84 mmol) anddi-tert-butyl diethylphosphoramidite (0.33 g; 1.34 mmol) in dry THF (5.5ml). After 5 minutes, the solution was cooled to −78° C. and a solutionof m-chloroperbenzoic acid (0.375 g; 1.68 mmol) in dichloromethane (3ml) was added in portions. The mixture was allowed to warm to ambienttemperature and further stirred for 5 minutes. After addition of aqueousammonium hydrogen carbonate and aqueous sodium sulphite, the organicsolvent was removed by evaporation and the residue was taken up indichloromethane. The organic phase was washed with water, dried andevaporated. The residue was purified by flash chromatography elutingwith ethyl acetate/methanol (95/5) to give (1) as a foam.

Yield: 54%.

¹H NMR spectrum (DMSOd₆): 1.03 (t, 3H); 1.43 (s, 18H); 1.72 (m, 1H); 2.0(m, 1H); 2.35 (m, 1H); 2.50 (m, 3H, signal obscured by DMSO peak);3.2–3.6 (m, 1H signal obscured by H₂O peak); 3.50 (s, 3H); 3.78 (s, 3H);3.84 (s, 3H); 4.99 (m, 2H); 6.80 (s, 1H); 7.35 (m, 2H).

EXAMPLE 28

12N Hydrochloric acid (5 ml) was added to a solution of(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-tertbutoxypropanamide(1) (0.35 g; 0.7 mmol) in 1,4-dioxane (5 ml). The mixture was heated at60° C. under argon atmosphere for 1 hour. After dilution with ether, theresulting precipitate was filtered, washed with ether and dried to give(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-hydroxypropanamideas a white solid.

Yield: 65%

¹H NMR spectrum (DMSOd₆): 1.90 (s, 3H); 1.95 (, 1H); 2.05 (m, 1H); 2.18(m, 1H); 2.50 (m, 1H, signal obscured by DMSO peak); 3.48 (s, 3H); 3.79(s, 3H); 3.84 (s, 3H); 3.88 (m, 2H); 4.05 (m, 1H); 4.45 (m, 1H); 6.8 (s,1H); 7.29 (d, 1H); 7.58 (d, 1H); 7.65 (dd, 1H); 8.32 (br s, 3H); 8.47(d, 1H).

MS-ESI: 444 [MH]⁺

The starting materials was prepared as follows:

O-(7-(Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.468 g; 1.28 mmol) andN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(2) (0.398 g; 1.12 mmol) were added to a solution ofN-fmoc-O-tert-butyl-1-serine (0.428 g; 1.12 mmol) in dichloromethane (18ml) and N,N-diisopropylethylamine (0.222 ml; 1.28 mmol). The mixture wasstirred overnight under argon atmosphere at ambient temperature. Afteraddition of water, the organic phase was dried over MgSO₄ and evaporatedto give(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-(fmoc-amino)-3-(tertbutoxy)propanamide(3).

Yield: 95%

¹H NMR spectrum (DMSOd₆): 1.14 (s, 9H); 1.87 (s, 3H); 1.80 (m, 1H);2.0–2.2 (m, 2H); 2.5 (m, 1H, signal obscured by DMSO peak); 3.46 (s,3H); 3.50–3.60 (m, 2H); 3.77 (s, 3H); 3.82 (s, 3H); 4.20–4.35 (m, 4H);4.45 (m, 1H); 6.77 (s, 1H); 7.25 (d, 1H); 7.32 (m, 2H); 7.42 (m, 2H);7.54 (m, 2H); 7.61 (s, 1H); 7.76 (m, 2H); 7.89 (m, 2H); 8.40 (d, 1H).

MS-ESI: 744 [MNa]⁺

A solution of (3) (0.75 g; 1.04 mmol) and piperidine (1 ml) indichloromethane (1.5 ml) was stirred at ambient temperature for 45minutes. After evaporation to dryness the residue was purified by flashchromatography eluting with ethyl acetate/methanol (95/5) to give (1) asa foam.

Yield: 70%

¹H NMR spectrum (DMSOd₆): 1.14 (s, 9H); 1.87 (s, 3H); 1.89 (m, 1H);1.90–2.15 (m, 2H); 2.5 (m, 1H, signal obscured by DMSO peak); 3.46 (s,3H); 3.40–3.50 (m, 3H); 3.77 (s, 3H); 3.82 (s, 3H); 4.49 (m, 1H); 6.77(s, 1H); 7.25 (d, 1H); 7.58 (m, 2H); 8.39 (d, 1H).

MS-ESI: 500.2 [MH]⁺

EXAMPLE 29

Oxalyl chloride (0.44 g; 3.4 mmol) and DMF (50 μl) were added to asuspension ofN-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) under argon atmosphere (1.15 g; 3 mmol) in dichloromethane (10 ml).The mixture was stirred at ambient temperature for 2 hours, evaporatedto dryness and redissolved in dichloromethane (20 ml). The solution wascooled at −78° C. and ammonia gas was allowed to bubble through thesolution for 5 minutes. The mixture was allowed to warm up and furtherstirred at ambient temperature for 15 minutes. After evaporation todryness, the residue was taken up in aqueous sodium hydrogencarbonate/ethyl acetate. The organic phase was separated, evaporated andpurified by flash chromatography eluting with ethyl acetate/methanol(95/5) to giveN-[(5S)-3-carbamoyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 20%

¹H NMR spectrum (DMSOd₆): 1.89 (s, 3H); 1.89 (m, 1H); 1.96 (m, 1H); 2.5(m, 1H, signal obscured by DMSO peak); 3.49 (s, 3H); 3.78 (s, 3H); 3.84(s, 3H); 4.54 (m, 1H); 6.81 (s, 1H); 7.36 (d, 1H); 7.78 (dd, 1H); 7.87(d, 1H); 7.96 (s, 1H); 8.47 (d, 1H).

MS-ESI: 407 [MNa]⁺

EXAMPLE 30

Trichloromethyl chloroformate (0.094 ml; 0.77 mmol) was added inportions at 0° C. to a solution ofN-[(5S)-3-carbamoyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(0.2 g; 0.484 mmol), (prepared as described for Example 29) andtrimethyl phosphate (0.306 ml; 2.6 mmol). The mixture was allowed towarm up and then heated at 60° C. for 5 minutes. The reaction mixturewas poured onto ice and stirred. The resulting precipitate was filtered,dried and purified by flash chromatography, eluting withdichloromethane/ethyl acetate (1/1) to giveN-[(5S)-3-cyano-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 61%.

¹H NMR spectrum (DMSOd₆): 0.97 (t, 3H); 1.60 (m, 1H); 1.95 (m, 2H); 2.30(m, 2H); 2.45 (m, 1H, signal partially obscured by DMSO peak); 3.46 (s,3H); 3.76 (s, 3H); 3.83 (s, 3H); 4.54 (m, 2H); 5.16 (t, 1H); 6.75 (s,1H); 7.15–7.30 (m, 2H); 7.53 (s, 1H).

MS-ESI: 358 [MH]⁺

EXAMPLE 31

A solution ofN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.3 g; 84 mmol) and glutaric anhydride (0.199 g; 84 mmol) indichloromethane (20 ml) was stirred at ambient temperature for 90minutes. After removal of the solvent by evaporation, the residue waspurified by flash chromatography, eluting with dichloromethane/methanol(80/20) to give, after trituration in ether,N-[(5S)-3-(4-carboxybutanoylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a white solid.

Yield: 63%

¹H NMR spectrum (DMSOd₆): 1.8–2 (m, 3H); 1.88 (s, 3H); 2–2.25 (m, 2H);2.26 (t, 2H); 2.36 (t, 2H); 2.5 (s, 1H, signal partially observed byDMSO peak); 3.46 (s, 3H); 3.77 (s, 3H); 3.82 (s, 3H); 4.48 (m, 1H); 6.76(s, 1H); 7.22 (d, 1H); 7.53 (d, 1H); 7.56 (s, 1H); 8.4 (d, 1H); 9.97 (s,1H).

MS-ESI: 471 [MH]⁺

Elemental analysis Found C 59.2 H 6.2 N 5.4 C₂₅H₃₀N₂O₇ Requires C 63.8 H6.4 N 6.0%

EXAMPLE 32

A suspension of 4-aminobutyric acid (0.111 g; 1.08 mmol) andN,O-bis(trimethylsilyl)acetamide (1.8 ml; 7.3 mmol) in dichloromethane(10 ml) was stirred at ambient temperature for 2 hours. The mixture wasevaporated to dryness and redissolved in dichloromethane (10 ml) underargon atmosphere. A solution ofN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(0.35 g; 0.98 mmol), phenyl chloroformate (135 μl; 1.08 mmol) andtriethylamine (151 μl; 1.08 mmol) in dichloromethane (10 ml) was stirredfor 1 hour under argon atmosphere and added to the above solution. Themixture was stirred overnight, evaporated and purified by preparativeHPLC on reverse phase silica eluting with a 0–30% gradient ofmethanol/ammonium carbonate buffer pH7 to give, after evaporation,4-[([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]aminocarbonyl)amino]butanoicacid as a solid

Yield: 50%

¹H NMR spectrum (DMSOd₆, CF₃CO₂D): 1.68 (m, 2H); 1.88 (s, 3H); 1.85–2(m, 1H); 2–2.2 (m, 2H); 2.27 (m, 2H); 2.5 (m, 1H, signal partiallyobserved by DMSO peak); 3.12 (m, 2H); 3.47 (s, 3H); 3.78 (s, 3H); 3.83(s, 3H); 4.48 (m, 1H); 6.75 (s, 1H); 7.17 (d, 1H); 7.3 (s, 1H); 7.39 (d,1H).

MS-ESI: 486 [MH]⁺

Elemental analysis Found C 58.3 H 6.5 N 8.7 C₂₅H₃₁N₃O₇ Requires C 61.8 H6.4 N 8.7%

EXAMPLE 33

A solution ofN-[(5S)-3-phenoxycarbonyloxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.35 g; 0.73 mmol), 2-aminomethanesulphonic acid (0.156 g; 1.25mmol) and triethylamine (174 μl; 1.25 mmol) in DMSO (2.5 ml) was heatedat 70° C. for 2 days. The mixture was taken up in water and purified bypreparative HPLC eluting with a 0–30% gradient of methanol/ammoniumcarbonate buffer (2 g/l pH7). The appropriate fractions were evaporatedand the resulting solid triturated in ether and dried to give2-[([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxycarbonyl)amino]ethane-1-sulphonicacid.

Yield: 22%

¹H NMR spectrum (DMSOd₆; CF₃CO₂D): 1.89 (s, 3H); 1.8–1.95 (m, 1H); 2–2.5(m, 2H); 2.5 (m, 1H, signal partially obscured by DMSO peak); 2.71 (t,2H); 3.4 (m, 2H); 3.54 (s, 3H); 3.8 (s, 3H); 3.85 (s, 3H); 4.58 (m, 1H);6.8 (s, 1H); 7.08 (d, 1H); 7.1 (s, 1H); 7.32 (d, 1H).

MS-ESI: 509 [MH]⁺

Elemental analysis: Found C 48.1 H 6.0 N 7.3 S 5.2 C₂₃H₂₈N₂O₉S; RequiresC 48.4 H 6.4 N 7.4 S 5.6% 1 NH₃, 2.5 H₂O

The starting material was prepared as follows:

A solution of N-acetyl colchicinol (0.35 g; 0.98 mmol), phenylchloroformate (145 μl; 1.08 mmol) and triethylamine (150 μl; 1.08 mmol)in dichloromethane (20 ml) was stirred at ambient temperature for 1hour. The mixture was washed with water and the organic phaseevaporated. The residue was purified by flash chromatography, elutingwith ethyl acetate/petroleum ether (80/20) to giveN-[(5S)-3-phenoxycarbonyloxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideas a foam.

Yield: 79%

¹H NMR spectrum (DMSOd₆): 1.89 (s, 3H); 1.8–1.95 (m, 1H); 2–2.3 (m, 2H);2.5 (m 1H, signal partially obscured by DMSO peak); 3.52 (s, 3H); 3.78(s, 3H); 3.84 (s, 3H); 4.58 (m, 1H); 6.8 (s, 1H); 7.2–7.6 (m, 8H); 8.41(d, 1H).

EXAMPLE 34

A solution of N-acetyl-cochicinol (0.25 g; 0.7 mmol), 4-nitrophenylchloroformate (0.169 g; 0.84 mmol) and triethylamine (117 μl; 0.84 mmol)in dichloromethane (10 ml) was stirred under argon atmosphere for 1hour. N-Acetylethylenediamine (0.086 g; 0.84 mmol) was then added andthe mixture was stirred further for 3 hours. After evaporation todryness, the residue was purified by flash chromatography, eluting withmethanol/acetonitrile/dichloromethane (4/48/48) to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylN-[2-(acetylamino)ethyl]carbamate.

Yield: 49%

¹H NMR spectrum (DMSOd₆): 1.84 (s, 3H); 1.88 (s, 3H); 1.85–1.95 (m, 1H);2–2.25 (m, 2H); 2.5 (m, 1H, signal partially observed by H₂O peak); 3.53(s, 3H); 3.79 (s, 3H); 3.85 (s, 3H); 4.55 (m, 1H); 6.81 (s, 1H); 7.06(dd, 1H); 7.07 (d, 1H); 7.32 (d, 1H); 7.79 (m, 1H); 7.8 (m, 1H); 8.41(d, 1H).

MS-ESI: 486.1 [MH]⁺

Elemental analysis Found C 60.3 H 6.6 N 8.3 C₂₅H₃₁N₃O₇ 0.6 H₂O RequiresC 60.5 H 6.5 N 8.5%

EXAMPLE 35

A suspension of 4-aminobutyric acid (0.087 g; 0.84 mmol) andN,O-bis(trimethylsilyl)acetamide (0.865 ml; 3.5 mmol) in dichloromethane(10 ml) was stirred under argon atmosphere for 3 hours and evaporated todryness. The residue was then redissolved in dichloromethane (10 ml).4-Nitrophenyl chloroformate (0.17 g; 0.84 mmol) and triethylamine (0.117ml; 0.84 mmol) were added to a solution of N-acetyl-colchicinol (0.25 g;0.7 mmol) in dichloromethane (10 ml). The solution was stirred for 1hour and added to the above solution. The resulting mixture was stirredfurther for 3 hours. After evaporation to dryness the residue waspurified by preparative HPLC on reverse phase silica eluting withmethanol/ammonium carbonate buffer (2 g/l pH7) (30/70) to give, afterevaporation of the appropriate fractions,4-[([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxycarbonyl)amino]butanoicacid.

Yield: 44%

¹H NMR spectrum (DMSOd₆, CF₃CO₂D): 1.73 (m, 2H); 1.88 (s, 3H); 1.8–1.95(m, 1H); 2–2.25 (m, 2H); 2.3 (m, 2H); 2.5 (m, 1H, signal partiallyobscured by DMSO peak); 3.11 (m, 2H); 3.53 (s, 3H); 3.79 (s, 3H); 3.84(s, 3H); 4.45 (m, 1H); 6.8 (s, 1H); 7.05 (dd, 1H); 7.07 (d, 1H); 7.31(d, 1H); 7.87 (m, 1H); 8.42 (d, 1H).

MS-ESI: 487.1 [MH]⁺

Elemental analysis Found C 60.2 H 6.3 N 6.0 C₂₅H₃₀N₂O₈ 0.5 H₂O RequiresC 60.6 H 6.3 N 5.7%

EXAMPLE 36

A mixture ofN-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.3 g; 0.78 mmol), DCCI (0.193 g; 0.93 mmol), DMAP (0.019 g; 0.15mmol) and N-acetylethylenediamine (0.096 g; 0.985 mmol) indichloromethane was stirred at ambient temperature overnight. Afterevaporation of the solvent, the residue was purified by flashchromatography and eluted with methanol/dichloromethane (10/90) to giveN-[(5S)-3-(2-acetylaminoethylcarbamoyl)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 71%

¹H NMR spectrum (DMSOd₆): 1.82 (s, 3H); 1.89 (s, 3H); 1.85–2.05 (m, 2H);2.17 (m, 1H); 2.5 (m, 1H, signal partially obscured by DMSO peak); 3.22(m, 2H); 3.32 (m, 2H, signal partially observed by H₂O peak); 3.49 (s,3H); 3.79 (s, 3H); 3.84 (s, 3H); 4.55 (m, 1H); 6.81 (s, 1H); 7.38 (d,1H); 7.75 (dd, 1H); 7.84 (d, 1H); 8 (m, 1H); 8.52 (m, 2H).

MS-ESI: 470.2 [MH]⁺

Elemental analysis: Found C 60.3 H 6.6 N 8.2 C₂₅H₃₁N₃O₆ 0.4dichloromethane Requires C 60.6 H 6.4 N 8.4%

EXAMPLE 37

A solution of6-[({[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy}carbonyl)amino]-2-(benzyloxycarbonylamino)-hexanoicacid (1) (0.4 g; 0.6 mmol) in ethanol (80 ml) was hydrogenated in thepresence of 10% palladium on carbon (0.08 g). After filtration of thecatalyst and evaporation to dryness, the residue was purified bypreparative HPLC eluting with a 0–40% gradient of methanol/ammoniumcarbonate buffer (2 g/l pH7) to give, after evaporation and triturationin ether,6-[({[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy}carbonyl)amino]-2-aminohexanoicacid as a solid.

Yield: 75%

¹H NMR spectrum (DMSOd₆): 1.35–1.55 -m, 4H); 1.62 (m, 1H); 1.72 (m, 1H);1.9 (s, 3H); 1.9 (m, 1H); 2.05 (m, 1H); 2.15 (m, 1H); 2.5 (m, 1H, signalpartially obscured by DMSO peak); 3–3.2 (m, 3H); 3.51 (s, 3H); 3.78 (s,3H); 3.83 (s, 3H); 4.55 (m, 1H); 6.79 (s, 1H); 7.02 (dd, 1H); 7.12 (d,1H); 7.29 (d, 1H); 7.74 (m, 1H); 8.7 (d, 1H).

MS-ESI: 530.1 [MH]⁺

Elemental analysis: Found C 60.2 H 7.0 N 7.8 C₂₇H₃₅N₃O₉ 0.5 H₂O RequiresC 60.2 H 6.7 N 7.8%

The starting material was prepared as follows:

A suspension of N-(carboxybenzyloxy)-L-lysine (0.141 g; 0.5 mmol) andN,O-bis(trimethylsilyl)acetamide (0.519 ml; 2 mmol) in dichloromethane(10 ml) was stirred at ambient temperature under argon atmosphere for 3hours. The mixture was evaporated to dryness and the residue redissolvedin dichloromethane (10 ml). A solution of N-acetyl-colchicinol (0.15 g;0.42 mmol), and 4-nitrophenyl chloroformate (0.102 g; 0.5 mmol) wasstirred at ambient temperature for 1 hour and then added to the abovesolution. The resulting mixture was stirred overnight, evaporated todryness and purified by preparative HPLC eluting with a 0–55% gradientof methanol/ammonium carbonate buffer (2 g/l pH7) to give (1).

Yield: 63%

¹H NMR spectrum (DMSOd₆): 1.35 (m, 2H); 1.49 (m, 2H); 1.62 (m, 1H); 1.72(m, 1H); 1.89 (s, 3H); 1.9 (m, 1H); 2.07 (m, 1H); 2.15 (m, 1H); 2.5 (m,1H, signal partially obscured by DMSO peak); 3.07 (m, 2H); 3.52 (s, 3H);3.8 (s, 3H); 3.85 (s, 3H); 4.57 (m, 1H); 5.05 (m, 2H); 6.81 (s, 1H); 7(m, 1H); 7.05 (dd, 1H); 7.1 (d, 1H); 7.32 (d, 1H); 7.3–7.4 (m, 5H); 7.75(m, 1H; 8.58 (d, 1H).

EXAMPLE 38

A solution ofN-([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxymethyl)-2-chloroacetamide(1) (0.25 g; 0.55 mmol) in morpholine (2 ml)) was stirred at ambienttemperature for 2 hours. After addition of dichloromethane and removalof the insoluble material by filtration, the filtrate was evaporated todryness and the residue was purified by preparative HPLC eluting with a0–45% gradient of ethanol/ammonium carbonate buffer (2 g/l pH7) to give,after evaporation and trituration in ether,N-([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxymethyl)-2-morpholinoacetamide.

Yield: 60%

¹H NMR spectrum (DMSOd₆): 1.85 (m, 1H); 1.88 (s, 3H); 1.95–2.2 (m, 2H);2.4 (m, 4H); 2.5 (m, 1H, signal partially observed by DMSO peak); 3 (s,2H); 3.47 (s, 3H); 3.57 (m, 4H); 3.77 (s, 3H); 3.82 (s, 3H); 4.5 (m,1H); 5.18 (m, 2H); 6.76 (s, 1H); 6.91 (d, 1H); 6.98 (dd, 1H); 7.22 (d,1H); 8.32 (m, 1H); 8.85 (m, 1H).

MS-ESI: 514.1 [MH]⁺

Elemental analysis Found C 61.2 H 6.9 N 7.9 C₂₇H₃₅N₃O₇ Requires C 61.4 H7.0 N 8.0%

The starting material was prepared as follows:

2-Chloro-N-(hydroxymethyl)-acetamide (0.342 g; 2.7 mmol),triphenylphosphine (1.1 g; 4.19 mmol) and DEAD (0.6 ml; 4.19 mmol) wereadded to a solution of N-acetyl-colchicinol (0.3 g; 0.84 mmol) indichloromethane (20 ml) under argon atmosphere. The mixture was stirredat ambient temperature for 2 hours, evaporated and purified by flashchromatography eluting with ethyl acetate/dichloromethane (50/50) anddichloromethane/methanol (98/2) to give (1).

Yield: 76%

MS-ESI: 485.1 [MH]⁺

EXAMPLE 39

N-[(5S)-3-(2-tertButoxycarbonylethylcarbamoyl)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.26 g; 0.5 mmol) in solution in dichloromethane (10 ml) wastreated with TFA (10 ml) at ambient temperature for 1 hour. Afterevaporation to dryness, the residue was purified by preparative HPLCeluting with methanol/ammonium carbonate buffer (2 g/l pH7) (35/65) togive, after evaporation and trituration in ether,3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylcarbonylamino]propanoicacid as a white solid.

Yield: 56%

¹H NMR spectrum (DMSOd₆): 1.91 (s, 3H); 1.85–2.1 (m, 2H); 2.2 (m, 1H);2.5 (m, 1H, signal partially observed by DMSO peak); 3.2–3.6 (m, 4H,signal partially obscured by H₂O peak); 3.5 (s, 3H); 3.8 (s, 3H); 3.86(s, 3H); 4.6 (m, 1H); 6.82 (s, 1H); 7.39 (d, 1H); 7.74 (dd, 1H); 7.85(d, 1H); 8.54 (d, 1H); 8.62 (m, 1H).

MS-ESI: 457.1 [MH]⁺

Elemental analysis: Found C 60.9 H 6.7 N 6.7 C₂₄H₂₈N₂O₇ Requires C 63.2H 6.2 N 6.1%

The starting material was prepared as follows:

A mixture ofN-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(1) (0.3 g; 0.78 mmol), EDCI (0.179 g; 0.93 mmol), DMAP (0.019 g; 0.15mmol), triethylamine (0.13 ml; 0.985 mmol) and tertbutyl3-methylaminopropanoate (0.17 g; 0.985 mmol) in dichloromethane wasstirred at ambient temperature overnight. After removal of the solventby evaporation, the residue was purified by flash chromatography andeluted with ethyl acetate to give (1).

Yield: 84%

¹H NMR spectrum (DMSOd₆): 1.4 (s, 9H); 1.89 (s, 3H); 1.9 (m, 1H); 2 (m,1H); 2.17 (m, 1H); 2.5 (m, 1H, signal partially obscured by DMSO peak);3.25–3.55 (m, 4H); 3.49 (s, 3H); 3.78 (s, 3H); 3.84 (s, 3H); 4.55 (m,1H); 6.81 (s, 1H); 7.37 (d, 1H); 7.7 (dd, 1H); 7.81 (d, 1H); 8.5 (m,2H).

EXAMPLE 40

A suspension of 3-(4-methylpiperazin-1-ylcarbonyl)propanoic acid (2)(0.219 g; 1.1 mmol), DCCI (0.226 ml; 1.1 mmol) and DMAP (0.052 ml; 0.42mmol) in dichloromethane (20 ml) was stirred under argon atmosphere for1 hour. N-Acetyl-colchicinol (0.3 g; 0.84 mmol) was then added and themixture was stirred overnight. After removal of the insoluble materialby filtration, the filtrate was evaporated and purified by preparativeHPLC eluting with a 0–50% gradient of methanol/ammonium carbonate buffer(2 g/l pH7) to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-[4-methylpiperazin-1-ylcarbonyl]propanoate.

Yield: 48%

¹H NMR spectrum (DMSOd₆): 1.80–1.96 (m, 1H); 1.88 (s, 3H); 2.07 (m, 1H);2.18 (m, 1H); 2.20 (s, 3H); 2.26 (m, 2H); 2.33 (m, 2H); 2.59 (m, 1H,signal partially obscured by DMSO peak); 2.73 (m, 2H); 2.79 (m, 2H);3.48 (m, 4H); 3.53 (s, 3H); 3.80 (s, 3H); 3.86 (s, 3H); 4.55 (m, 1H);6.82 (s, 1H); 7.03–7.12 (m, 2H); 7.36 (d, 1H); 8.43 (d, 1H).

MS-ESI: 540 [MH]⁺

Elemental analysis Found C 63.9 H 7.1 N 7.5 C₂₉H₃₇N₃O₇; 0.3 H₂O RequiresC 63.9 H 7.0 N 7.7%

The starting material was prepared as follows:

A suspension of N-methylpiperazine (1.1 ml; 10 mmol) and succinicanhydride (1.2 g; 12 mmol) in dichloromethane (20 ml) was stirred underargon atmosphere for 24 hours. After evaporation to dryness, the residuewas triturated in ether/pentane to give (2) as a solid.

Yield: 91%

¹H NMR Spectrum (DMSOd₆): 2.37 (s, 3H); 2.53 (m, 2H); 2.58 (m, 2H); 2.64(m, 4H); 3.59 (m, 2H); 3.69 (m, 2H); 5.70 (br s, 1H).

EXAMPLE 41

N-Acetyl-colchicinol (0.3 g; 0.84 mmol) was added under argon atmosphereto a solution of adipic acid (0.147 g; 1 mmol,O-(7-(azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.383 g; 1 mmol) and diisopropylethylamine (0.352ml; 2 mmol) in acetonitrile (20 ml). The reaction mixture was stirred atambient temperature overnight and evaporated to dryness. The residue wastaken up in water (4 ml), the pH was adjusted to 6.5 with 0.1Mhydrochloric acid. The solution was purified by preparative HPLC elutingwith a 0–40% gradient of methanol/ammonium carbonate buffer (2 g/l pH7)to give5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoicacid.

Yield: 31%

¹H NMR spectrum (DMSOd₆): 1.54–1.75 (m, 4H); 1.85–1.90 (m, 1H); 1.87 (s,3H); 1.98–2.28 (m, 4H); 2.57 (m, 1H, signal partially obscured by DMSOpeak); 2.61 (t, 2H); 3.51 (s, 3H); 3.78 (s, 3H); 3.84 (s, 3H); 4.55 (m,1H); 6.80 (s, 1H); 7.04–7.11 (m, 2H); 7.34 (d, 1H); 8.43 (d, 1H).

MS-ESI: 508 [MNa]⁺

EXAMPLE 42

Chlorosulphonic acid (1 ml) was added at 0° C. in portions to a solutionof pyridine (10 ml). After 15 minutes at 0° C., a solution ofN-acetyl-colchicinol (1 g, 2.8 mmol) in pyridine (10 ml) was added. Thesolution was stirred overnight at ambient temperature. Water (30 ml) wasadded and the mixture was adjusted to pH8 by addition of sodium hydrogencarbonate. The aqueous layer was extracted with ether (3×20 ml) andpurified on HP20SS resin, eluted with a 0–40% gradient ofmethanol/water. The volatiles were removed by evaporation to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylhydrogen sulphate as a white solid.

Yield=71%

¹H NMR spectrum (DMSOd₆): 1.9 (s, 3H), 2–2.2 (m, 2H), 2.5 (m, 1H, signalobscured by DMSO peak), 3.5 (s, 3H), 3.77 (s, 3H), 3.83 (s, 3H), 4.5 (m,1H), 6.77 (s, 1H), 7.1 (s, 1H), 7.2 (2s, 2H), 8.4 (d, 1H).

MS-ESI: 482 [M Na]⁺

Elemental analysis: Found C 48.1 H 4.9 N 2.8 S 6.2 C₂₀H₂₂O₈NSNa, 2 H₂ORequires C 48.5 H 5.3 N 2.8 S 6.5%

EXAMPLE 43

Using an analogous procedure to that described for Example 27[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methylditertbutyl phosphate was treated with 1M hydrogen chloride in1,4-dioxane to give[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methyldihydrogen phosphate.

Yield: 95%

The sodium salt was prepared by addition of 2N sodium hydroxide to asuspension of[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methyldihydrogen phosphate in water until the mixture was at pH7. Afterfreeze-drying, the sodium salt was obtained as a white solid.

¹H NMR Spectrum (D₂O): 1.94 (m, 1H); 1.98 (s, 3H); 2.15 (m, 1H); 2.25(m, 1H); 2.50 (m, 1H); 3.50 (s, 3H); 3.80 (s, 3H); 3.84 (s, 3H); 4.48(m, 1H); 4.80 (m, 2H); 6.80 (s, 1H); 7.40 (m, 3H).

MS-ESI: 496 [MH]⁺

The starting material was prepared as follows:

Using an analogous procedure to that described for the starting materialin Example 27,N-[(5S)-3-hydroxymethyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,(prepared as described in Example 25), was reacted with di-tert-butyldiethylphosphoramidite to give[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]methylditertbutyl phosphate.

Yield: 59%

¹H NMR spectrum (DMSOd₆): 1.432 (s, 9H); 1.435 (s, 9H); 1.88 (s, 3H);1.90 (m, 1H); 2.02 (m, 1H); 2.18 (m, 1H); 2.5 (m, 1H, signal obscured byDMSO peak); 3.50 (s, 3H); 3.79 (s, 3H); 3.85 (s, 3H); 4.56 (m, 1H); 4.97(d, 2H); 6.81 (s, 1H); 7.35 (m, 2H); 7.38 (s, 1H); 8.46 (d, 1H).

EXAMPLE 44

A solution of methyl(2S,3R,4S,5R,6R)-6-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3,4,5-tris(isobutyryloxy)tetrahydro-2H-pyran-2-carboxylate(1) (515 mg; 0.68 mol) in methanol (10 ml) and water (1 ml) was treatedwith lithium hydroxide monohydrate (214 mg; 5.1 mmol). The reactionmixture was stirred at ambient temperature and additional solution oflithium hydroxide monohydrate (86 mg; 2 mmol) in H₂O (1 ml) was addedafter 12 hours and then again after a further 10 hours hours to completethe reaction. After a total of 30 hours at ambient temperature, themethanol was removed and the remaining solution was adjusted to pH6 with2N hydrochloric acid. The resulting heterogeneous solution was depositedon a column of HP2O SS resin (35 ml) for purification, eluting with a 0to 75% aqueous solution of methanol. After removal of the solvents byevaporation, the solid was purified further by preparative HPLC onreverse phase silica eluting with a 0–50% gradient of methanol/water togive, after removal of the methanol by evaporation and freeze drying,(2S,3S,4S,5R,6R)-6-{[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy}-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylicacid as a white solid (260 mg).

Yield: 68%

¹H NMR spectrum (DMSOd₆, CF₃CO₂D): 1.88 (m, 1H); 1.89 (s, 3H); 2.08 (m,1H); 2.15 (m, 1H); 2.52 (m, 1H, signal obscured partially by DMSO peak);3.25–3.36 (m, 3H); 3.44 (t, 1H); 3.51 (s, 3H); 3.78 (s, 3H); 3.84 (s,3H); 3.91 (d, 1H); 4.50 (m, 1H); 5.03 (d, 1H); 6.77 (s, 1H); 6.98 (s,1H); 7.00 (d, 1H); 7.26 (d, 1H).

MS-ESI: 534 [MH]⁺

Elemental analysis Found C 55.7 H 6.1 N 2.5 C₂₆H₃₁NO₁₁; 1.5 H₂O RequiresC 56.0 H 5.9 N 2.6%

The starting material was prepared as follows:

Freshly distilled boron trifluoride-diethyl ether (0.22 ml; 1.7 mmol)was added at 0° C. under argon atmosphere to a stirred solution ofN-acetyl-colchicinol (2) (303 mg; 0.85 mmol) and methyl(trichloroacetimidoyl 2,3,4-tri-O-isobutyryl-α-D-glucopyranosid) uronate(3) (955 mg; 1.7 mmol), (THL 36, 8601, 1995), in dichloromethane (8 ml).The mixture was stirred at 0° C. for 15 minutes and then at ambienttemperature for 2 hours. The reaction mixture was diluted withdichloromethane, washed with aqueous saturated sodium hydrogencarbonate, water, then dried (MgSO₄) and evaporated. The residue waspurified by flash chromatography eluting with a 0 to 35% gradient ofdichloromethane/ether to give, after evaporation, (1) as a lightyellow-green foam.

Yield: 82%

¹H NMR spectrum (DMSOd₆+CD₃CO₂D): 1.01–1.06 (m, 18H); 1.87 (m, 1H); 1.89(s, 3H); 2.13 (m, 1H); 2.26 (m, 1H); 2.50 (m, 4H, signal obscuredpartially by DMSO peak); 3.50 (s, 3H); 3.65 (s, 3H); 3.78 (s, 3H); 3.83(s, 3H); 4.58 (m, 1H); 4.74 (d, 1H); 5.11 (t, 1H); 5.17 (d, 1H); 5.60(t, 1H); 5.73 (d, 1H); 6.77 (s, 1H); 6.94 (s, 1H); 6.95 (d, 1H); 7.28(d, 1H); 8.37 (d, 1H).

MS-ESI: 758 [MH]⁺

EXAMPLE 45

(2R,3R,4S,5R,6R)-2-[(5S)-5-(Acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3,5-bis(isobutyryloxy)-6-[(isobutyryloxy)methyl]tetrahydro-2H-pyran-4-yl2-methylpropanoate (1) (304 mg; 0.38 mmol) and H₂O (0.25 ml) were addedto a 0.48M solution of lithium hydroxide monohydrate in methanol (6 ml).The mixture was stirred at ambient temperature for 6 hours. Afterremoval of the methanol by evaporation, the remaining aqueous solutionwas adjusted to pH6.2 with 2N hydrochloric acid. The resultingheterogeneous solution was deposited on a column of HP2O SS resin (35ml) for purification, eluting with a 0–60% gradient of methanol/water.After concentration and freeze dryingN-((5S)-9,10,11-trimethoxy-3-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)acetamide was obtained as a white solid (180 mg).

Yield: 84%

¹H NMR spectrum (DMSOd₆, CF₃CO₂D): 1.88 (m, 1H); 1.90 (s, 3H); 2.10 (m,1H); 2.18 (m, 1H); 2.52 (m, 1H, signal obscured partially by DMSO peak);3.21–3.37 (m, 4H); 3.51 (s, 3H); 3.48–3.58 (m, 1H); 3.74–3.81 (m, 1H);3.80 (s, 3H); 3.84 (s, 3H); 4.50 (m, 1H); 4.92 (d, 1H); 6.78 (s, 1H);6.98 (d, 1H); 7.00 (dd, 1H); 7.26 (d, 1H); 8.36 (d, 1H).

MS-ESI: 542 [MNa]⁺

Elemental analysis Found C 55.3 H 6.6 N 2.6 C₂₆H₃₃NO₁₀ 2.6 H₂O RequiredC 55.1 H 6.8 N 2.5%

The starting material was prepared as follows:

N-Benzyltributylammomium bromide (523 mg; 1 mmol) andN-acetyl-colchicinol (2) (357 mg; 1 mmol) in a 1.25N aqueous solution ofsodium hydroxide were added at 0° C. to a solution of the(2R,3R,4S,5S,6R)-2-bromo-3,5-bis(isobutyryloxy)-6-[(isobutyryloxy)methyl]tetrahydro-2H-pyran-4-yl2-methylpropanoate (3) (523 mg; 1 mmol), (J. Chem. Soc. Perkins Trans. 11995 p 577), in trichloromethane (2 ml). After 1 hour the reactionmixture was stirred at ambient temperature. Additional reagent (3) (250mg; 0.48 mmol and 1.33 mg; 0.33 mmol) and 1.25N sodium hydroxide (0.2 mland 0.1 ml) were added to the reaction mixture after 6 hours at ambienttemperature and then again after a further 14 hours at ambienttemperature. After a total of 24 hours, the reaction mixture was dilutedwith dichloromethane, washed successively with water, brine and thendried (MgSO₄). After removal of the solvent, the residue was purified byflash chromatography eluting with dichloromethane/ether (8/2 to 6/4) togive (1) (320 mg) as a foam.

Yield: 40%

¹H NMR spectrum (DMSOd₆): 1.00–1.11 (m, 24H); 1.88 (m, 1H); 1.89 (s,3H); 2.08 (m, 1H); 2.21 (m, 1H); 2.46–2.66 (m, 5H, signal obscuredpartially by DMSO peak); 3.48 (s, 3H); 377 (s, 3H); 3.83 (s, 3H);4.16–4.24 (m, 2H); 4.32 (m, 1H); 4.47 (m, 1H); 5.08 (m, 2H); 5.54 (t,1H); 5.67 (d, 1H); 6.77 (s, 1H); 6.92 (d, 1H); 6.95 (dd, 1H); 7.25 (d,1H); 8.38 (d, 1H).

MS-ESI: 800 [MH]⁺

EXAMPLE 46

A solution of N-acetyl-colchicinol (1) (0.45 g; 1.26 mmol) in THF (40ml) under argon was cooled to 0° C. and treated with a 1.0M solution oflithiumHMDS in THF (1.39 ml; 1.39 mmol). The mixture was stirred at 0°C. for 1 hour and then added in portions over about 15 minutes to asolution of methyl dichlorophosphate (625 μl; 4.16 mmol) in THF (150ml). The mixture was stirred at ambient temperature for 15 minutes.After addition of water (200 ml) the THF was removed by evaporation.After removal of the insoluble material by filtration, the filtrate waspurified on HP20 SS resin eluting with a gradient of 0–60%methanol/water. The appropriate fractions were freeze-dried to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylmethyl hydrogen phosphate as white solid (391 mg).

Yield: 69%

¹H NMR spectrum (DMSO d₆; CF₃CO₂D): 1.89 (s, 3H); 1.9 (m, 1H); 2.05 (m,1H); 2.18 (m, 1H); 2.5 (m, 1H, signal obscured partially by DMSO peak);3.53 (s, 3H); 3.73 (d, 3H); 3.79 (s, 3H); 3.84 (s, 3H); 4.51 (m, 1H);6.79 (s, 1H); 7.14 (d, 1H); 7.15 (s, 1H); 7.32 (d, 1H); 8.46 (d, 1H).

MS-ESI: 451 [MH]⁺

Elemental analysis: Found C 54.1 H 5.9 N 3.1 C₂₁H₂₆NO₈P; 0.7 H₂ORequires C 54.2 H 6.0 N 3.0%

EXAMPLE 47

A solution of N-acetyl-colchicinol (1) (0.36 g; 1.0 mmol) in THF (40 ml)under argon was cooled to 0° C. and treated with a 1.0M solution oflithiumHMDS in THF (1.1 ml; 1.1 mmol). The mixture was stirred at 0° C.for 1 hour and then added in portions over about 2 hours to a solutionof ethyl dichlorophosphate (400 μl; 3.3 mmol) in THF (150 ml). Themixture was stirred at ambient temperature for 15 minutes. Afteraddition of water (200 ml) the THF was removed by evaporation. Afterremoval of the insoluble material by filtration, the filtrate waspurified on HP20 SS resin eluting with a gradient of 0–60%methanol/water. The appropriate fractions were freeze-dried to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylethyl hydrogen phosphate as a white solid (259 mg).

Yield: 56%

¹H NMR spectrum (DMSO d₆; CF₃CO₂D): 1.25 (dt, 3H); 1.89 (s, 3H); 1.9 (m,1H); 2.05 (m, 1H); 2.19 (m, 1H); 2.5 (m, 1H, signal obscured partiallyby DMSO peak); 3.53 (s, 3H); 3.79 (s, 3H); 3.85 (s, 3H); 4.09 (m, 2H);4.52 (m, 1H); 6.80 (s, 1H); 7.13 (d, 1H); 7.15 (s, 1H); 7.32 (d, 1H);8.45 (d, 1H).

MS-ESI: 466 [MH]⁺

Elemental analysis: Found C 54.6 H 6.0 N 3.0 C₂₂H₂₈NO₈P; 1.0 H₂ORequires C 54.7 H 6.3 N 2.9%

EXAMPLE 48

Triethylamine (140 μl; 1.0 mmol) and methyl chloroformate (80 μl; 1.0mmol) were added to a solution of5-hydroxy-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol(1) (0.18 g; 0.5 mmol) in THF (10 ml). The mixture was stirred atambient temperature overnight. After removal of the insoluble materialby filtration the residue was purified by flash chromatography elutingwith increasingly polar mixtures of ethyl acetate/hexanes (5 to 60%ethyl acetate) to give5-hydroxy-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylmethyl carbonate as a hard oil/white solid (163 mg).

Yield: 81%

¹H NMR spectrum (CDCl₃): 1.89 (m, 1H); 2.39 (m, 2H); 2.54 (m, 1H); 3.61(s, 3H); 3.87 (s, 3H); 3.91 (s, 3H); 3.92 (s, 3H); 3.93 (s, 3H); 4.56(m, 1H); 6.59 (s, 1H); 7.15 (s, 1H); 7.45 (s, 1H).

MS-ESI: 427 [MNa]⁺

EXAMPLE 49

Triethylamine (35 μl; 0.225 mmol) and methyl chloroformate (20 μl; 0.225mmol) were added to a solution of3-hydroxy-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-one(1) (0.052 g; 0.15 mmol) in THF (5 ml). The mixture was stirred atambient temperature for 5 hours. After removal of the insoluble materialby filtration the residue was purified by flash chromatography elutingwith increasingly polar mixtures of ethyl acetate/hexanes (0 to 100%ethyl acetate) to give methyl2,9,10,11-tetramethoxy-5-oxo-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylcarbonate as a white solid (57 mg).

Yield: 95%

¹H NMR spectrum (CDCl₃): 2.69 (m, 1H); 2.85 (m, 1H); 2.97 (m, 1H); 3.16(m, 1H); 3.53 (s, 3H); 3.93 (s, 3H); 3.94 (s, 3H); 3.94 (s, 3H); 3.95(s, 3H); 6.64 (s, 1H); 7.24 (s, 1H); 7.47 (s, 1H).

MS-ESI: 403 [MH]⁺

Elemental analysis: Found C 62.0 H 5.5 C₂₁H₂₂O₈; 0.2 H₂O Requires C 62.1H 5.6%

The starting material was prepared as follows:

Triethylamine (1.05 ml; 7.5 mmol) and acetyl chloride (540 μl; 7.5 mmol)were added to a solution of5-hydroxy-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol(2) (1.05 g; 3.0 mmol) in THF (50 ml). The mixture was stirred atambient temperature overnight. After removal of the insoluble materialby filtration the residue was purified by flash chromatography elutingwith increasingly polar mixtures of ethyl acetate/hexanes (0 to 100%ethyl acetate) to give methyl5-hydroxy-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylcarboxylate (3) as a white solid (880 mg).

Yield: 76%

¹H NMR spectrum (CDCl₃): 1.89 (m, 1H); 2.34 (s, 3H); 2.38 (m, 2H); 2.53(m, 1H); 3.61 (s, 3H); 3.84 (s, 3H); 3.90 (s, 3H); 3.91 (s, 3H); 4.55(m, 1H); 6.59 (s, 1H); 7.14 (s, 1H); 7.35 (s, 1H).

MS-ESI: 411 [MNa]⁺

Elemental analysis: Found C 65.0 H 6.3 C₂₁H₂₄O₇ Requires C 64.9 H 6.2%

A solution of (3) (0.776 g; 2.0 mmol) in dichloromethane (30 ml) wasadded to a solution of Collins Reagent (3.1 g; 12.0 mmol) indichloromethane (30 ml). The mixture was stirred at ambient temperaturefor 30 minutes. After removal of the insoluble material by filtrationthe filtrate was washed with 2N hydrochloric acid, then brine and driedover MgSO₄. The residue was purified by flash chromatography elutingwith increasingly polar mixtures of ethyl acetate/hexanes (0 to 60%ethyl acetate) to give methyl5-oxo-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylcarboxylate (4) as a white solid (706 mg).

Yield: 91%

¹H NMR spectrum (CDCl₃): 2.34 (s, 3H); 2.64 (m, 1H); 2.82 (m, 1H); 2.93(m, 1H); 3.14 (m, 1H); 3.50 (s, 3H); 3.88 (s, 3H); 3.91 (s, 3H); 3.92(s, 3H); 6.61 (s, 1H); 7.20 (s, 1H); 7.36 (s, 1H).

MS-ESI: 387 [MH]⁺

Elemental analysis: Found C 65.6 H 6.0 C₂₁H₂₂O₇ Requires C 65.3 H 5.7%

Water (10 ml) and saturated aqueous sodium hydrogen carbonate (10 ml)were added to a solution of (4) (0.58 g; 1.5 mmol) in methanol (50 ml).The mixture was stirred at ambient temperature overnight. After dilutionwith ethyl acetate the organic phase was washed with 2N hydrochloricacid, then brine and dried over MgSO₄. The residue was triturated withether and hexanes to give (1) as a white solid (441 mg).

Yield: 85%

¹H NMR spectrum (CDCl₃): 2.61 (m, 1H); 2.80 (m, 1H); 2.91 (m, 1H); 3.06(m, 1H); 3.45 (s, 3H); 3.88 (s, 3H); 3.88 (s, 3H); 3.91 (s, 3H); 5.73 (sbr, 1H); 6.58 (s, 1H); 7.09 (s, 1H); 7.17 (s, 1H).

MS-ESI: 345 [MH]⁺

Elemental analysis: Found C 65.52 H 6.10 C₁₉H₂₀O₆; 0.2 H₂O Requires C65.58 H 5.91

EXAMPLE 50

Triethylamine (18 μl; 0.12 mmol) and methyl chloroformate (10 μl; 0.12mmol) were added to a solution of5-(hydroxyimino)-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ol(1) (0.035 g; 0.1 mmol) in THF (3 ml). The mixture was stirred atambient temperature overnight. After removal of the insoluble materialby filtration the residue was purified by flash chromatography elutingwith increasingly polar mixtures of ethyl acetate/hexanes (0 to 100%ethyl acetate) to give5-(hydroxyimino)-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylmethyl carbonate (E isomer) as a white solid (22 mg), followed by thesecond (Z) isomer (7 mg).

Yield: 54%

¹H NMR spectrum (CDCl₃): 2.59 (m, 1H); 2.82 (m, 2H); 3.20 (m, 1H); 3.51(s, 3H); 3.88 (s, 3H); 3.90 (s, 3H); 3.91 (s, 3H); 3.93 (s 3H); 6.59 (s,1H); 7.21 (s, 1H); 7.26 (s, 1H); 8.61 (br s, 1H).

MS-ESI: 418 [MH]⁺

Elemental analysis: Found C 58.1 H 5.7 N 3.0 C₂₁H₂₃NO₈; 0.8 H₂O RequiresC 58.4 H 5.7 N 3.2%

The starting material was prepared as follows:

Hydroxylamine hydrochloride (70 mg; 1.0 mmol) was added to a solution of3-hydroxy-2,9,10,11-tetramethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-one(2) (0.172 g; 0.5 mmol) in pyridine (3.0 ml). The mixture was stirred atambient temperature overnight. After dilution with 2N hydrochloric acidand extraction with ethyl acetate, the organic phase was washed with 2Nhydrochloric acid, then brine and dried over MgSO₄. The residue wastriturated with ether and hexanes to give (1) (a 3:1 mixture of E:Zisomers) as a white solid (170 mg).

Yield: 95%

¹H NMR spectrum (CDCl₃), major isomer: 2.56 (m, 1H); 2.66–2.9 (m, 2H);3.18 (m, 1H); 3.45 (s, 3H); 3.86 (s, 3H); 3.88 (s, 3H); 3.89 (s, 3H);6.55 (s, 1H); 7.08 (s, 1H); 7.24 (s, 1H).

MS-ESI: 360 [MH]⁺

Elemental analysis: Found C 62.6 H 6.3 N 3.6 C₁₉H₂₁NO₆; 0.3 H₂O RequiresC 62.6 H 6.0 N 3.8%

EXAMPLE 51

A solution ofN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(0.712 g; 2 mmol) in ethanol (3.75 ml) and 36% hydrochloric acid (1.57ml) was slowly added into a mixture of ice (6 ml) and 36% hydrochloricacid (1.57 ml). At 0° C. a solution of sodium nitrite (0.14 g; 2 mmol)in water (0.25 ml) was added. The mixture was stirred at 0° C. for 1hour and then transferred into a separate flask containing a solution ofcopper(I) chloride (0.218 g; 2.2 mmol) in water (0.35 ml) and 36%hydrochloric acid (0.4 ml). The resulting mixture was stirred at 30° C.for 30 minutes and extracted with toluene/ethyl acetate (50/50). Theorganic phase was washed with water, dilute sodium hydroxide, andsaturated sodium chloride solution, then dried and the volatiles wereremoved by evaporation. The residue was purified by flash chromatographyeluting with ethyl acetate to giveN-[(5S)-3-chloro-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.

Yield: 46%.

¹H NMR Spectrum (DMSOd₆): 1.89 (s, 3H); 1.90 (m, 1H); 2.02 (m, 1H); 2.15(m, 1H); 2.5 (m, 1H); 3.50 (s, 3H); 3.78 (s, 3H); 3.84 (s, 3H); 4.52 (m,1H); 6.80 (s, 1H); 7.35 (m, 3H); 8.43 (d, 1H).

MS-ESI: 398 [MNa]⁺

EXAMPLE 52

A solution of(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-(N-tertbutoxycarbonylamino)-5-[(2-nitroethanimidoyl)amino]pentanamide(1) (0.15 g, 0.28 mmol) in dichloromethane (2 ml) was treated at 0° C.with TFA (2 ml). The mixture was stirred at ambient temperature for 2hours and evaporated. The residue was taken up inmethanol/dichloromethane and evaporated to give an oil which wastriturated in ether to give(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-5-[(2-nitroethanimidoyl)amino]pentanamideas a solid.

Yield: 95%

¹H NMR spectrum (DMSOd₆): 1.60 (m, 2H); 1.83 (m, 2H); 1.90 (s, 3H); 1.92(m, 1H); 2.06 (m, 1H); 2.20 (m, 1H); 2.5 (m, 1H; signal obscured by DMSOPeak); 3.22 (m, 2H); 3.50 (s, 3H); 3.79 (s, 3H); 3.85 (s, 3H); 3.95 (m,1H); 4.48 (m, 1H); 6.80 (s, 1H); 7.32 (d, (1H); 7.45 (d, 1H); 7.75 (dd,1H); 8.45 (d, 1H).

MS-ESI: 558 [MH]⁺

Elemental analysis Found C 48.1 H 5.7 N 13.2 C₂₆H₃₅N₇O₇; 1.4 TFA; 0.5methanol Requires C 48.0 H 5.3 N 13.4%

The starting material was prepared as follows:

A solution ofN-[(5S)-3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide(2) (0.45 g; 1.26 mmol), Nα-tert-butoxycarbonyl-ω-nitro-L-arginine(50.402 g; 1.26 mmol), EDCI (0.312 g; 1.63 mmol) and DMAP (0.03 g; 0.25mmol) in dichloromethane (18 ml) was stirred at ambient temperatureovernight. After addition of water (2 ml) and extraction, the organicphase was evaporated to give an oil which was purified by flashchromatography eluting with ethyl acetate/methanol (95/5) to give (1).

Yield: 28%

¹H NMR (DMSOd₆): 1.38 (m, 2H); 1.40 (s, 9H); 1.60 (m, 2H); 1.90 (s, 3H);1.91 (m, 1H); 2.15 (m, 2H); 2.5 (m, 2H, signal obscured by DMSO peak);3.20 (m, 2H); 3.48 (s, 3H); 3.79 (s, 3H); 3.84 (s, 3H); 4.13 (m, 1H);4.50 (m, 1H); 6.80 (s, 1H); 7.10 (d, 1H); 7.27 (d, 2H); 7.55 (s, 1H);7.62 (d, 1H); 8.40 (d, 1H).

MS-ESI: 658 [MH]⁺

EXAMPLE 53

A solution of N-acetyl-colchicinol (0.36 g; 1.0 mmol) in THF (40 ml)under argon was cooled to 0° C. and treated with a 1.0M solution oflithiumHMDS in THF (1.1 ml; 1.1 mmol). The mixture was stirred at 0° C.for 1 hour and then added in portions over about 2 hours to a solutionof methylphosphonic dichloride (0.53 mg; 4.0 mmol) in THF (150 ml). Themixture was stirred at ambient temperature for 15 minutes. Afteraddition of water (200 ml) the THF was removed by evaporation. Afterremoval of the insoluble material by filtration, the filtrate waspurified on HP20 SS resin eluting with a gradient of 0–60%methanol/water. The methanol was removed by evaporation and the mixturewas adjusted to pH7.14 with sodium hydroxide (0.1 M). The appropriatefractions were freeze-dried to give(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-ylhydrogen methylphosphonate as a beige solid (180 mg).

Yield: 41%

¹H NMR spectrum (DMSO d₆; CF₃CO₂D): 1.53 (d, 3H); 1.88 (s, 3H); 1.9 (m,1H); 2.06 (m, 1H); 2.16 (m, 1H); 2.5 (m, 1H, signal obscured partiallyby DMSO peak); 3.52 (s, 3H); 3.78 (s, 3H); 3.84 (s, 3H); 4.51 (m, 1H);6.79 (s, 1H); 7.13 (s, 1H); 7.14 (d, 1H); 7.30 d, 1H); 8.45 (d, 1H).

MS-ESI: 458 [MNa]⁺

EXAMPLE 54

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c)Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellosesodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0(d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesiumstearate 1.5 (e) Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodiumhydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f)Injection II 10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100% (1mg/ml, (g) Injection III buffered to pH 6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100%Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)–(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

1. A compound of the formula IIa:

wherein X is —CH(R⁷)— wherein R⁷ is hydrogen, hydroxy, C₁₋₇alkoxy, —OR⁸or —NR⁸R⁹, wherein R⁸ is a group —Y¹R¹⁰, wherein Y¹ is a direct bond,—C(O)—, —C(S)—, —S—, —C(O)O—, —C(O)NR¹¹—, —SO₂— or —SO₂NR¹²— (whereinR¹¹ and R¹², which may be the same or different, each independentlyrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ isselected from one of the following nine groups: 1) hydrogen, C₁₋₇alkyl,C₃₋₇cycloalkyl, C₁₋₄alkylY⁸C₁₋₄alkyl wherein Y⁸ is as defined herein, orphenyl, which alkyl, cycloalkyl, alkylY⁸alkyl or phenyl group may bearone or more substituents selected from: halogeno, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, hydroxy, carboxy, carbamoyl, C₁₋₄alkoxy,C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino,C₁₋₄alkanoyl, phenyl, nitro, sulphate, phosphate, Z¹, wherein Z¹represents a 5–6 membered saturated heterocyclic group (linked viacarbon or nitrogen) with 1–2 heteroatoms, selected independently from O,S and N, which heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,C₁₋₄aminoalkyl, C₁₋₇alkanoyl, cyanoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkylZ¹ (wherein Z¹ is as definedherein), and a group —Y²R¹³, wherein Y² is —NR¹⁴C(O)— or —O—C(O)—(wherein R¹⁴ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR¹³ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R¹⁵ wherein R¹⁵ is a phenylgroup or a 5–10-membered aromatic heterocyclic group (linked via carbonor nitrogen) with 1–4 heteroatoms selected independently from O, N andS, which phenyl or aromatic heterocyclic group may bear one or moresubstituents selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR¹⁶R¹⁷ and—NR¹⁸COR¹⁹ (wherein R¹⁶, R¹⁷, R¹⁸ and R¹⁹, which may be the same ordifferent, each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);2) R¹⁵ wherein R¹⁵ is as defined herein; 3) C₂₋₇alkenylR¹⁵ (wherein R¹⁵is as defined herein); 4) C₃₋₇alkynylR¹⁵ (wherein R¹⁵ is as definedherein); 5) Z¹ (wherein Z¹ is as defined herein); 6) C₁₋₇alkylZ¹(wherein Z¹ is as defined herein); 7) C₁₋₇alkylY⁸Z¹, wherein Z¹ is asdefined herein and Y⁸ is —C(O)—, —NR⁵⁹C(O)—, —NR⁵⁹C(O)C₁₋₄alkyl-,—C(O)NR⁶⁰— or —C(O)NR⁶⁰C₁₋₄alkyl-, (wherein R⁵⁹ and R⁶⁰, which may bethe same or different, each represents hydrogen, C₁₋₃alkyl,C₁₋₃hydroxyalkyl or C₁₋₃alkoxyC₂₋₃alkyl); 8) (C₁₋₇alkyl)_(c)Y⁹Z³,wherein c is 0 or 1, Z³ is an amino acid group and Y⁹ is a direct bond,—C(O)— or —NR⁶¹— (wherein R⁶¹ is hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl); and 9) C₁₋₇alkylR¹⁵ (wherein R¹⁵ is as definedherein); and R⁹ is hydrogen, C₁₋₇alkyl or C₃₋₇cycloalkyl, which alkyl orcycloalkyl group may bear one or more substituents selected fromC₁₋₄alkoxy and phenyl; R¹, R² and R³ are each independently hydrogen,PO₃H₂, sulphate, C₃₋₇cycloalkyl, C₂₋₇alkenyl, C₂₋₇alkynyl, C₁₋₇alkanoyl,a group R²⁰C₁₋₇alkyl (wherein R²⁰ is phenyl which may bear one or moresubstituents selected from C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄aminoalkyl andC₁₋₄hydroxyalkoxy), C₁₋₇alkyl or C₁₋₇alkylsulphonyl, which alkyl oralkylsulphonyl group may bear one or more substituents selected from:halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, hydroxy,C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, nitro, sulphate,phosphate and a group —Y²R²¹, wherein Y² is —NR²²C(O)— or —O—C(O)—(wherein R²² represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²¹ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R²³ wherein R²³ is a phenylgroup or a 5–10-membered aromatic heterocyclic group (linked via carbonor nitrogen) with 1–4 heteroatoms selected independently from O, N andS, which phenyl or aromatic heterocyclic group may bear one or moresubstituents selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR²⁴R²⁵ and—NR²⁶COR²⁷ (wherein R²⁴, R²⁵, R²⁶ and R²⁷, which may be the same ordifferent, each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);with the proviso that at least two of R¹, R² and R³ are C₁₋₇alkyl; R⁴ ishydrogen, cyano, halogeno, nitro, amino, hydroxy, C₁₋₇alkoxy,C₁₋₇thioalkoxy, C₁₋₇alkanoyl or C₁₋₇alkyl, which alkyl group may bearone or more substituents selected from: halogeno, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl,C₁₋₄alkylsulphonyl, C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy,phenyl, nitro, sulphate, phosphate and a group —Y³R²⁸, wherein Y³ is—NR²⁹C(O)— or —O—C(O)— (wherein R²⁹ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R³⁰wherein R³⁰ is a phenyl group or a 5–10-membered aromatic heterocyclicgroup (linked via carbon or nitrogen) with 1–4 heteroatoms selectedindependently from O, N and S, which phenyl or aromatic heterocyclicgroup may bear one or more substituents selected from hydroxy, nitro,halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano,—CONR³¹R³² and —NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴, which may bethe same or different, each represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl); R⁵ and R⁶ are each independently selected fromhydrogen, —OPO₃H₂, phosphonate, cyano, halogeno, nitro, amino, carboxy,carbamoyl, hydroxy, C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇thioalkoxy, C₁₋₇alkyl,which alkyl group may bear one or more substituents selected from:halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, hydroxy,C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, sulphate,phosphate and a group —Y³R²⁸, wherein Y³ is —NR²⁹C(O)— or —O—C(O)—(wherein R²⁹ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²⁸ is C₁₋₇alkyl, C₃₋₇cycloalkyl or a group R³⁰ wherein R³⁰ is a phenylgroup or a 5–10-membered aromatic heterocyclic group (linked via carbonor nitrogen) with 1–4 heteroatoms selected independently from O, N andS, which phenyl or aromatic heterocyclic group may bear one or moresubstituents selected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR³¹R³² and—NR³¹COR³² (wherein R³¹, R³², R³³ and R³⁴, which may be the same ordifferent, each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl),and a group —Y⁴R³⁵, wherein Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —SO₂—,—OSO₂—, —NR³⁶—, —C₁₋₄alkylNR³⁶—, —C₁₋₄alkylC(O)—, —NR³⁷C(O)—, —OC(O)O—,—C(O)NR³⁸— or —NR³⁹C(O)O— (wherein R³⁶, R³⁷, R³⁸ and R³⁹, which may bethe same or different, each represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³⁵ is a sugar moiety, a mono-peptide, adi-peptide, a tri-peptide, a tetra-peptide, sulphate, hydroxy, amino,C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl, C₁₋₇alkylamino, di(C₁₋₇alkyl)amino,aminoC₁₋₇alkylamino, C₁₋₇alkylaminoC₁₋₇alkylamino,C₁₋₇alkanoylaminoC₁₋₇alkyl, di(C₁₋₇alkyl)aminoC₁₋₇alkylamino,C₁₋₇alkylphosphate, C₁₋₇alkylphosphonate, C₁₋₇alkylcarbamoylC₁₋₇alkyl,which alkyl, alkoxy, alkanoyl, alkylamino, dialkylamino,aminoalkylamino, alkylaminoalkylamino, alkanoylaminoalkyl,dialkylaminoalkylamino, alkylphosphate, alkylphosphate oralkylcarbamoylalkyl, may bear one or more substituents selected from:halogeno, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, hydroxy,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphonyl,C₁₋₄alkoxycarbonylamino, C₁₋₄alkanoyl, carboxy, phenyl, nitro, sulphate,phosphate and a group —Y⁵R⁴⁰, wherein Y⁵ is —NR⁴¹C(O)—, —C(O)NR⁴²—,—C(O)—O— or —O—C(O)— (wherein R⁴¹ and R⁴² which may be the same ordifferent each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R⁴⁰ is C₁₋₇alkyl, C₃₋₇cycloalkyl, carboxyC₁₋₇alkyl or a group R⁴³wherein R⁴³ is a phenyl group, a benzyl group or a 5–10-memberedaromatic heterocyclic group (linked via carbon or nitrogen) with 1–4heteroatoms selected independently from O, N and S, which phenyl, benzylor aromatic heterocyclic group may bear one or more substituentsselected from hydroxy, nitro, halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,C₁₋₄hydroxyalkoxy, carboxy, cyano, —CONR⁴⁴R⁴⁵ and —NR⁴⁶COR⁴⁷ (whereinR⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷, which may be the same or different, eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl), R⁴⁸, wherein R⁴⁸is a phenyl group, a benzyl group or a 5–10-membered aromaticheterocyclic group (linked via carbon or nitrogen) with 1–4 heteroatomsselected independently from O, N and S, which phenyl, benzyl or aromaticheterocyclic group may bear one or more substituents selected fromhydroxy, nitro, halogeno, amino, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy, carboxy,C₁₋₄carboxyalkyl, phenyl, cyano, —CONR⁴⁹R⁵⁰, —NR⁵¹COR⁵² (wherein R⁴⁹,R⁵⁰, R⁵¹ and R⁵², which may be the same or different, each representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (whereinR⁵³ is as defined herein), C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as definedherein), R⁵³, wherein R⁵³ is a 5–6-membered saturated heterocyclic group(linked via carbon or nitrogen) with 1–2 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴, wherein R⁵⁴ is a 5–6-memberedsaturated heterocyclic group (linked via carbon or nitrogen) with 1–2heteroatoms, selected independently from O, S and N, which heterocyclicgroup may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl andC₁₋₄alkylsulphonylC₁₋₄alkyl, or (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³, wherein R⁵³ isas defined herein, a is 0, or an integer 1–4, b is 0 or an integer 1–4and Y⁶ represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or—C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same ordifferent, each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl),and wherein one or more of the (CH₂)_(a) or (CH₂)_(b) groups may bearone or more substituents selected from hydroxy, amino and halogeno; withthe proviso that R⁵ is not hydroxy, alkoxy, substituted alkoxy (whereinR⁵ is Y⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one or moresubstituents selected from the list given herein), —OPO₃H₂,—O—C₁₋₇alkanoyl or benzyloxy; with the further proviso that at least oneof R⁵ or R⁶ is a group —Y⁴R³⁵ (wherein Y⁴ and R³⁵ are as defined herein)but with the further provisos that when R⁵ is —Y⁴R³⁵ and R⁶ is hydrogen,hydroxy, methoxy or methoxycarbonyl, —Y⁴R³⁵ is not selected from caseswherein: Y⁴ is —C(O)—, —OC(O)—, —O—, —SO—, —OSO₂—, —NR³⁶—, —NR³⁷C(O)— or—C(O)NR³⁸— (wherein R³⁶, R³⁷ and R³⁸, which may be the same ordifferent, each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³⁵ is a glycine, valine or lysine group, a dipeptide of glycine andvaline groups, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl, (which alkyl, alkoxyor alkanoyl may bear one or more substituents selected from: halogeno,hydroxy, and a group —Y⁵R⁴⁰ (wherein Y⁵ is —O—C(O)— and R⁴⁰ isC₁₋₇alkyl), or R⁴⁸, wherein R⁴⁸ is a tetrazolyl group (which may or maynot be substituted as herein defined), a phenyl group or a benzyl groupwhich phenyl or benzyl group may bear one or more substituents selectedfrom C₁₋₄alkyl; and that when R⁶ is —Y⁴R³⁵ and R⁵ is hydrogen, methoxyor methoxycarbonyl, —Y⁴R³⁵ is not selected from cases wherein: Y⁴ is—C(O)—, —O— or —OSO₂— and R³⁵ is C₁₋₇alkyl, C₁₋₇alkoxy (which alkyl,alkoxy or alkanoyl may bear one or more substituents selected from:halogeno), R⁴⁸ (wherein R⁴⁸ is a benzyl group which benzyl group maybear one or more substituents selected from C₁₋₄alkyl), or R⁵³ (whereinR⁵³ is piperidinyl); or a salt thereof.
 2. A compound according to claim1 wherein X is —CH(R⁷)—, wherein R⁷ is —OR⁸ or —NR⁸R⁹, wherein R⁸ is agroup —Y¹R¹⁰ (wherein Y¹ is —C(O)—, —C(O)O— or —C(O)NR¹¹— (wherein R¹¹represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁰ is asdefined in claim 1) and R⁹ is as defined in claim
 1. 3. A compoundaccording to claim 1 wherein R¹, R² and R³ are each methyl.
 4. Acompound according to claim 1 wherein R⁴ is hydrogen.
 5. A compoundaccording to claim 1 wherein R⁶ is hydrogen, halogeno, amino, carboxy,hydroxy, C₁₋₇alkoxy or a group Y⁴R³⁵, wherein Y⁴ is —C(O)—, —O— or—OSO₂— and R³⁵ is C₁₋₇alkyl, C₁₋₇alkoxy (which alkyl or alkoxy may bearone or more substituents selected from halogeno), R⁴⁸ (wherein R⁴⁸ is abenzyl group) or R⁵³ (wherein R⁵³ is a 5–6-membered saturatedheterocyclic group (linked via carbon or nitrogen) with 1–2 heteroatomsselected independently from O, S and N).
 6. A compound according toclaim 1 wherein R⁶ is hydrogen, C(O)OCH₃ or methoxy.
 7. A compoundaccording to claim 1 wherein R⁵ is hydrogen, halogeno, amino, carboxy,carbamoyl, C₁₋₇alkanoyl, C₁₋₇thioalkoxy, or a group —Y⁴R³⁵, wherein Y⁴is —C(O)—, —OC(O)—, —O—, —SO—, —OSO₂—, —NR³⁶—, —NR³⁷C(O)— or —C(O)NR³⁸—(wherein R³⁶, R³⁷ and R³⁸, which may be the same or different, eachrepresents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³⁵ is asugar moiety, a mono-peptide, a di-peptide, a tri-peptide, atetra-peptide, C₁₋₇alkyl, C₁₋₇alkoxy, C₁₋₇alkanoyl,C₁₋₇alkanoylaminoC₁₋₇alkyl, which alkyl, alkoxy, alkanoyl,alkanoylaminoalkyl may bear one or more substituents selected from:halogeno, amino, hydroxy, carboxy, and a group —Y⁵R⁴⁰, wherein Y⁵ is—C(O)—O— or —O—C(O)— and R⁴⁰ is C₁₋₇alkyl or a group R⁴³ wherein R⁴³ isa benzyl group, R⁴⁸, wherein R⁴⁸ is a phenyl group, a benzyl group or a5–10-membered aromatic heterocyclic group (linked via carbon ornitrogen) with 1–4 heteroatoms selected independently from O, N and S,which phenyl, benzyl or aromatic heterocyclic group may bear one or moresubstituents selected from hydroxy, fluoro, amino, C₁₋₄alkoxy,C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, di(C₁₋₄hydroxyalkyl)aminoC₁₋₄alkyl,di(C₁₋₄aminoalkyl)aminoC₁₋₄alkyl, C₁₋₄hydroxyalkoxy, carboxy,C₁₋₄carboxyalkyl, cyano, —CONR⁴⁹R⁵⁰, —NR⁵¹COR⁵² (wherein R⁴⁹, R⁵⁰, R⁵¹and R⁵², which may be the same or different, each represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and C₁₋₄alkylR⁵³ (wherein R⁵³ is asdefined herein), C₁₋₇alkylR⁴⁸ (wherein R⁴⁸ is as defined herein), R⁵³,wherein R⁵³ is a 5–6-membered saturated heterocyclic group (linked viacarbon or nitrogen) with 1–2 heteroatoms, selected independently from O,S and N, which heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, fluoro, chloro, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄carboxyalkyl, C₁₋₄aminoalkyl,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkylsulphonylC₁₋₄alkyl and R⁵⁴, wherein R⁵⁴ is a 5–6-memberedsaturated heterocyclic group (linked via carbon or nitrogen) with 1–2heteroatoms, selected independently form O, S and N, which heterocyclicgroup may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl andC₁₋₄alkylsulphonylC₁₋₄alkyl, or (CH₂)_(a)Y⁶(CH₂)_(b)R⁵³, wherein R⁵³ isas defined herein, a is 0, or an integer 1–4, b is 0 or an integer 1–4and Y⁶ represents a direct bond, —O—, —C(O)—, —NR⁵⁵—, —NR⁵⁶C(O)— or—C(O)NR⁵⁷— (wherein R⁵⁵, R⁵⁶, and R⁵⁷, which may be the same ordifferent, each represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl),and wherein one or more of the (CH₂)_(a) or (CH₂)_(b) groups may bearone or more substituents selected from hydroxy, amino and halogeno; withthe proviso that R⁵ is not alkoxy, substituted alkoxy (wherein R⁵ isY⁴R³⁵ and Y⁴ is —O— and R³⁵ is C₁₋₇alkyl bearing one or moresubstituents selected from the list given herein), —O—C₁₋₇alkanoyl orbenzyloxy.
 8. A compound according to claim 1 selected from:(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-{[(2R)-2,6-diaminohexanoyl]amino}propanoate,(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-[(2-aminoacetyl)amino]propanoate,N-([(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxymethyl)-2-morpholinoacetamide,(2S,3S,4S,5R,6R)-6-{[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy}-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylicacid,N-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,N-[(5S)-3-(4-{morpholinomethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide,(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl3-[4-methylpiperazin-1-ylcarbonyl]propanoate,5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoicacid,4-(3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3-oxopropyl)benzoicacid and(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-hydroxypropanamide,and salts thereof.
 9. A compound according to claim 1 selected fromN-[(5S)-3-(4-{4-methylpiperazin-1-ylmethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamideand(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-3-hydroxypropanamide,and salts thereof.
 10. A compound according to claim 1 selected from(2S)-N-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]-2-amino-5-[(2-nitroethanimidoyl)amino]pentanamideand salts thereof.
 11. A process for the manufacture of a compound offormula IIa as defined in claim 1 which comprises: (a) for thepreparation of compounds of formula IIa and salts thereof in which R⁵ orR⁶ is a group Y⁴R³⁵ (wherein R³⁵ is as defined in claim 1 and Y⁴ is agroup —OC(O)— or —NHC(O)—), the reaction of a compound of formula III orIV:

 (wherein X, R¹, R², R³, R⁴, R⁵, R⁶ are as defined in claim 1 and Y⁷ is—O— or —NH—), by acylation or coupling reactions; (b) for thepreparation of compounds of formula IIa and salts thereof in which R⁵ orR⁶ is a group Y⁴R³⁵ (wherein R³⁵ is C₁₋₇alkoxy which may be substitutedas defined in claim 1 and Y⁴ is a group —OC(O)— or —NHC(O)—), thereaction of a compound of formula III and IV, by acylation reactions;(c) for the preparation of compounds of formula IIa and salts thereof inwhich R⁵ or R⁶ is a group Y⁴R³⁵ (wherein R³⁵ is aminoC₁₋₇alkylamino,C₁₋₇alkylaminoC₁₋₇alkylamino, di(C₁₋₇alkyl)aminoC₁₋₇alkylamino and maybe substituted as defined in claim 1, or is R⁵³ (wherein R⁵³ is asdefined in claim 1) and Y⁴ is a group —OC(O)— or —NHC(O)—), can beprepared by the reaction of a compound of formula III or IV, acylationreactions; (d) for the preparation of compounds of formula IIa and saltsthereof in which R⁵ or R⁶ is a group Y⁴R³⁵ (wherein R³⁵ is a sugarmoiety and Y⁴ is a group —O— or —NH—), the reaction of a compound offormula III or IV by glycosylation reactions; (e) for the preparation ofcompounds of formula IIa and salts thereof in which R⁵ or R⁶ is a groupY⁴R³⁵ (wherein R³⁵ is sulphate and Y⁴ is a group —O— or —NH—), thereaction of a compound of formula III or IV, by sulphonylationreactions; (f) for the preparation of compounds of formula IIa and saltsthereof in which R⁵ or R⁶ is a group Y⁴R³⁵ (wherein R³⁵ isC₁₋₇alkylphosphate and may be substituted as defined in claim 1 and Y⁴is a group —O— or —NH—), the reaction of a compound of formula III orIV, by phosphorylation reactions; (g) for the preparation of compoundsof formula IIa and salts thereof in which R⁵ is amino the reaction of acarboxylic acid of formula V:

 (wherein X, R¹, R², R³, R⁴ and R⁶ are as defined in claim 1) viaCurtius rearrangement and hydrolysis; and (h) for the preparation ofcompounds of formula IIa and salts thereof in which R⁵ or R⁶ is chlorothe reaction of a compound of formula III or IV by the Sandmeyerreaction; and when a pharmaceutically acceptable salt of a compound offormula IIa is required, reaction of the compound obtained with an acidor base whereby to obtain the desired pharmaceutically acceptable salt.12. A pharmaceutical composition which comprises as active ingredient acompound of formula IIa as defined in claim 1 or a pharmaceuticallyacceptable salt thereof in association with a pharmaceuticallyacceptable excipient or carrier.
 13. A method of reducingneovascularization by selectively damaging newly formed vascularendothelium in a warm-blooded animal in need thereof which comprisesadministering to said animal an effective amount of a compound offormula IIa or a pharmaceutically acceptable salt thereof as defined inany one of claims 1, 2, 5, 6, 7, 8, 9 and 10.